traitement naturel Intoxication au Nickel

Traitement naturel pour Intoxication au Nickel

Traitement naturel de l'intoxication au Nickel. Remèdes naturels pour lutter contre la carcinogénèse du Nickel. Cancer et Nickel, quel rapport ? L'exposition humaine à la pollution au nickel a le potentiel de créer...

Direction scientifique, Dr J. Burgos
Medecin - Acupuncture 

Mise à jour : 2022-03-21 10:54:59

Sommaire

Phytothérapie

Phytothérapie
Dossier selon Dr Rita MONSIEUR

Introduction au traitement naturel l'intoxication au Nickel

Le nickel est le  24ème élément naturel en abondance dans la croûte terrestre et distribué largement dans l'environnement.

Les principaux dépôts de minerai de nickel sont situés en Australie, au Canada, à Cuba, en Indonésie en Nouvelle Calédonie, et en Russie.                

Les sources naturelles de nickel atmosphérique sont  la poussière des émissions volcaniques, l'érosion des roches et des sols, la  combustion des carburants, l'émission lors d'extraction et de raffinage.

La consommation importante de produits contenant du nickel conduit inévitablement à la pollution  dans l'environnement par le nickel et  ses dérivés à tous les stades de la production, utilisation et distribution.

Contamination humaine et environnementale par le Nickel

Le nickel lixivie des emplacements de décharges et contribue à la contamination de la couche aquifère. Les pluies acides ont une tendance à mobiliser le nickel du sol et à augmenter la concentration en nickel des eaux souterraines avec consommation accrue chez les plantes, micro-organismes et animaux.

L'exposition du nickel se produit premièrement par l'inhalation et l'ingestion particulièrement élevées chez les travailleurs en métallurgie.

L'implantation d'endoprothèses contenant du nickel tels que prothèses orthopédiques, ponts dentaires, prothèses de valves cardiaques, fils de  stimulateur cardiaques  ainsi que les amalgames dentaires peuvent causer des perturbations immunologiques  autour de ces implants.

L'administration de médications contaminées par le nickel (albumine, produit de radiocontrast, produit d'hémodialyse)  augmente l'exposition parentérale de manière significative.

L'absorption cutanée du nickel, peut se produire par le port des bijoux, la manipulation de la monnaie ou d'outils fabriqués d'amalgames contenant du nickel.

L'ingestion de nickel lors de régimes riches en farine d'avoine, cacao, noix, produits de soja  peut atteindre 900µg par jour.

Dans les grandes villes et les régions industrielles, la concentration de nickel atmosphérique est en rapport avec les cendres volatiles de la combustion du carburant et des déchets, et peut atteindre jusqu'à  120-170 ng/m3 en comparaison de 6-17ng/m3 dans les régions urbaines.

La fumée de cigarette peut encore augmenter le nickel inhalé.

Une autre source de contamination est la consommation de produits végétaux qui peut atteindre jusqu'à 1mg  Ni /kg.

Effets de la contamination par le Nickel

Les risques de cancers respiratoires sont secondaires à des expositions à des concentrations  de nickel soluble au-delà de 1mg/m3 et non soluble  au-delà de  10mg/m3.

Contrairement aux composés insolubles, tels que le NiO, les sels solubles sont facilement absorbés par les tractus pulmonaires et digestifs, et moins par la peau.

La volatilité et la lipo-solubilité du nickel carbonyle Ni(CO)4 lui permettent de pénétrer les membranes des cellules, et sa réactivité réductrice contribue à sa toxicité élevée.

Le nickel carbonyle inhalé est rapidement absorbé par les poumons et entre dans les globules rouges où il est converti en Ni2+ et CO.

Dans le plasma humain, le Ni2+ est lié à des constituants ultrafiltrables : albumine, histidine, nickeloplasmine, une alpha 2-macroglobuline. Dans le cytosol des tissus, le nickel est lié à plusieurs protéines et peptides.

Effets cancérigènes du Nickel chez l'homme (dose dépendante ou non) 

La propension  des ouvriers du nickel à développer des cancers des cavités nasales a été rapportée la première fois par Bridge en 1933. Depuis des décennies plusieurs  résultats pilotes ont été confirmés par de nombreuses études épidémiologiques chez l'homme et  essais biologiques de carcinogenèse  chez les animaux.

Les études épidémiologiques montrent  une mortalité accrue chez les ouvriers de raffineries de nickel  par carcinomes, du poumon et des cavités nasales, liée à l'exposition chronique de poussières et de vapeurs de Ni lors de la torréfaction et de la fonte.

De même la soudure d'alliage de Ni, (par exemple l'acier inoxydable) peut être source de telles vapeurs.

Pendant des années l'on a cru qu'uniquement  les particules de poussières insolubles dans l'eau ( Ni3S2, NiO) étaient cancérogènes. Cependant, des données  épidémiologiques plus récentes, indiquent clairement que l'inhalation des composés de NiSO4 hydrosolubles, lors d'électroraffinage  sont aussi cancérigènes et  de manière doses dépendantes.

L'interaction entre le tabagisme et l'exposition au nickel semble  être additive plutôt  que multiplicative.

Parmi les 100 cancers sino nasaux de ces raffineries étudiées par Sunderman, 48% étaient des carcinomes des cellules squameuses, 39 % des carcinomes non différenciés et  6% d'adénocarcinomes.

Parmi les 259 cas de tumeurs des poumons 67% sont  des carcinomes de cellules squameuses.

Il n'y a aucune évidente épidémiologique de risque de cancer par l'environnement général ou exposition par le Ni alimentaire.

D'autres risques accrus, tels que, carcinomes du larynx, du rein, de la prostate, de l'estomac et sarcomes de tissus mous ont été notés,  mais la signification statistique de ces résultats est douteuse.

Sans compter que des expositions professionnelles - le nickel libéré par endoprothèses, plaques et vis de réparation osseuse ainsi que d'autres matériaux médicaux, et les amalgames contenant du nickel - ont été suspectées d'être la cause de tumeurs locales sporadiques, mais ceci n'est pas prouvée.

De façon générale, l'implantation de corps étranger, de cobalt métallique, de nickel métallique, d'un alliage de poudre se composant de 66-67%, de chrome de 13-16% et de fer de 7%,  a été récemment classifiée comme ‘' probablement cancérogène aux  humains ‘' (group2B) auprès du comité du CIRC (Centre International de Recherche sur le Cancer) soutenu  par le concept fondamental que les composés de nickel peuvent libérer des ions dans des sites critiques des cellules cibles

L'évaluation du CIRC conclue :

‘‘il y a une évidence suffisante chez l'homme pour la cancérogénicité du sulfate de nickel et des combinaisons de sulfures et d'oxydes dans l'industrie de raffinage du nickel (Groupe I), il y a une évidence insatisfaisante chez l'homme  pour la cancérogénicité du Ni métallique et alliages de nickel (Groupe 2B).''

Evaluation globale : les composés de Ni sont cancérigènes pour humains (Groupe 1).

Le nickel métallique est probablement cancérogène pour les humains (Groupe 2 B).

Stratégie d'action contre la carcinogénèse due au Nickel

Les effets génétiques et épi génétiques  du Ni2+  sont le résultat indirect  de la liaison du Ni2+ avec  des composants moléculaires de la cellule y compris des protéines de chromatine, et non d'un effet direct de formation mutagénique d'additif d'ADN.                                       

La co-administration de Ni3S2 et de métaux essentiels tels que Mg2+, Mn2+, Zn2+, Fe3+ (chez les animaux d'expérience),  résulte en une diminution de la carcinogenèse.

Cette concurrence du Ni avec les métaux essentiels pour les ligands communs et leurs sites de liaison peuvent être à la base  de l'inhibition observée de la carcinogenèse expérimentale de nickel par le  Mg 2+, Mn2+, Zn2+ et dans certains cas aussi le Fe2+ et le Ca2+.

Cependant, l'éventail le plus large possible des effets appropriés à la carcinogenèse, résulte de l'activité redox des complexes de Ni2+ avec certains ligands cellulaires, y compris des acides aminés, des peptides, des protéines, et d'autres molécules mais pas le DNA.

Les radicaux libres (l'anion superoxyde : O2- ; le peroxyde d'hydrogène : H2O2 ; le radical hydroxyl : OH) libérés  par réaction de ces complexes avec l'oxygène ambiant, sont capables de provoquer des endommagements  aux ligands mêmes et d'autres molécules.

C'est ainsi que si le complexe métallique est  situé dans la chromatine, c'est le cas de l'histone H3 et H2A, ROS peut être généré près du DNA et produire les différents types d'endommagement  oxydatif du DNA.

L'hypothèse épigénétique de la cancérogenèse au nickel, peut résulter uniquement  par formation de gènes silencieux tel que les gènes suppresseurs et de sénescence, même en absence de mutation.

Cette hypothèse intéressante  dans l'activité  (tumor-promoting) de faibles doses de nickel, est typique de la forme soluble.

La capacité génotoxique et mutagénique, responsable de l'altération du DNA pour des doses intracellulaires de Ni2+ élevées, sont mieux délivrées par phagocytose.                                                                                                                   

La cellule cible au Ni2+ inclus le système immunitaire entre autres par le système NF-kB.

Dans cette activation observée par la réponse inflammatoire au Ni2+, le stress oxydatif peut être augmenté. De même l'inhibition des cellules lymphocytaires NK (natural killer) par le métal peut supprimer la reconnaissance et l'élimination des cellules mutées.

La prévalence de la dermatite de contact au Ni est en croissance importante chez la femme et il y a une relation entre les pearcing et l'induction  de l'allergie  au nickel. 

Le mode de pearcing anticipe l'augmentation de la prévalence chez l‘homme.

L'allergie au nickel  associé au SFC avec ou sans auto-immunité est décrite pour la première fois par  le professeur  Stejskal en 1999 ( http://www.melisa.org/ ), en examinant l'hypersensibilité aux métaux lourds chez des patients à pathologies diverses compliquées de SFC et ou FM.

Les dermatites de contact, stomatites de contact, parodontites, lichen plan, résistance aux antibiotiques, sont décrites après sensibilisation aux métaux lourds.

L'inflammation résultante, peut se produire ailleurs dans l'organisme ou les métaux lourds sont déposés.

Chez ces patients souffrant de SFC la réaction lymphocytaire est augmentée de façon significative.

Elle constate une amélioration chez de nombreux patients après remplacement d'amalgames dentaires et élimination des métaux ; il n'y a aucune corrélation entre l'intensité, les plaintes et le nombre d'amalgames.

Les amalgames dentaires  sont en contact avec les muqueuses de la cavité dentaire pendant de nombreuses années. Le praticien doit choisir le moins corrosif, corrosion qui est augmentée par l'acidité, la plaque dentaire, la flore intra orale.

Il s'agit d'une base immunologique plutôt que toxicologique et génétiquement liée.

Pas uniquement la corrosion des amalgames dentaires mais aussi les implants orthopédiques, peuvent causer un rejet, une dermatite ou une mauvaise cicatrisation  chez les patients sensibilisés et pourraient causer des réactions systémiques et des symptômes généraux.

Le métal inoxydable (austénitique : Cr, Mo, Ni), représente un groupe résistant à la corrosion. Le métal libéré par ionisation, peut se déposer dans les tissus environnants d'où metalose, dés lors, le Ni,  phagocyté par les macrophages joue un rôle central dans le processus inflammatoire.

L'inhalation de la fumée de cigarette et l'absorption du nickel alimentaire  peuvent déclencher une allergie de type 4 et contribuer aux SFC et aux douleurs musculaires.

L'allergie au Ni avec regard sur des symptômes diffus et généraux tels que SFC et FM n'est pas totalement comprise et certainement sous-estimée.

Le patch test peut aggraver l'allergie existante.

Traitement naturel de lutte contre les effets cancérigènes du Nickel 

Une stratégie de détection de toute perturbation immunologique, comme le permet le test LTT (nom répandu Melisa), s'accompagnera d'une action thérapeutique visant concomitamment à ...

  • de détoxication métallique (SANS DEMINERALISER !) synergie entre Super Oxyde Dismutase, Extrait sec de Shitake (Lentinula edodes), L-Glutathion, Extrait sec de pépins de raisin (Vitis vinifera) titré en OPC, Chlorella (Chlorella vulgaris Beijerinck), Acide Lipoïque, Acetate de D alpha tocopheryle (Vit E ), Riboflavine (Vit B2), L- Sélénométhionine.,
  • d'inhibition de la carcinogenèse par apport de Acide ascorbique (vitamine C): 500 mg, Extrait d'echinacea purpurea : 25 mg, Extrait d'acérola : 16 mg, Vitamine A (acetate ) 400 µg (50%), Vitamine D3 (cholecalciferol) 5µg (100%) , Vitamine E ( Dalpha tocopherol acetate) 5.9 mg (49%) , Vitamine B1 (thiamine mononitrate) 0.5 mg (49%), Vitamine B2 (riboflavine) 0.7 mg (50%), vitamine B3 (nicotinamide) 8 mg (50%), Vitamine B5 (panthothenate calcium)3 mg (50%),Vitamine B6 (chlorhydrate de pyridoxine) 0.7 mg (49%), Vitamine B9 (acide folique) 100 µg (50%) , Vitamine B12 (cyanocobalamine) 1.2µg (50%) , Vitamine C (acide ascorbique): 39.5 mg (49%), Vitamine H (Biotine) 0.225 mg, Coenzyme Q10 3 mg, Fer (bisglycinate) 2.5 mg (18%), Cuivre (glycinate) 0.5 mg (50%), Iode (iodure de potassium) 37.5 µg (25%), Calcium (hydrogeno phosphate dicalcique) 60.3 mg, Manganèse(glycinate) 1 mg (50%), Selenium (selenomethionine) 27.3 µg (50%), chrome (picolinate) 10 µg (25%), Molybdène (molybdate sodique) 24.8 µg (50%), Zinc (sulfate de zinc L methionine) 2.5 mg (25%)
  • et une haute activité anti-oxydante association de Extrait de myrtille baies (vaccinium myrtillus) ;Extrait d'acerola (malpighia glabra) ; Extrait de pissenlit (taraxacum dens leonis ) ; SOD (super oxyde dismutase) ; GSH (glutathion réduit) ; Extrait de tomate (standardisé en lycopène) ; DL alpha tocophérol acétate; sulfate de zinc mono L-methionine ; L-selenomethionine ; Beta-carotène

Conclusion 

L'exposition humaine à la pollution au nickel, a le potentiel de créer une variété d'effets pathologiques comme, des allergies cutanées, de la fibrose pulmonaire, des pathologies cardiovasculaires et rénales dont la plus sérieuse est liée à l'activité cancérigène.

La fibromyalgie (FM) et le syndrome de fatigue chronique (SFC) sont aussi incriminés.

Le mécanisme exact  de la carcinogenèse induite par le nickel n'est pas connu et a  été le sujet de nombreuses investigations épidémiologiques et expérimentales. Le nickel particulièrement à haute dose a une propriété évidente d'activité mutagénique et génotoxique

Recherches associées à Traitement naturel de lutte contre les effets cancérigènes du Nickel : Nkl Pack, Tmd Labosp, comment tuer les métastases naturellement, 4 aliments qui détruisent les cellules cancéreuses, tuer les cellules cancéreuses naturellement, traitement naturel du cancer du cavum, remède miracle cancer, aliments qui tuent les cellules cancéreuses, remède cancer caché, cancer guérison naturelle 

Nos conseils et expérience en phytothérapie

produits naturels à prendre Préambule : Le choix des produits décrits ou des substances qui les composent est le fait de notre expérience et celle de nos confrères auteurs de leurs publications quant à leurs propriétés reconnues en phytothérapie en vue d'une aide réelle à la résolution de cette pathologie ; ces conseils sont délivrés à titre d'exemple, de façon non exhaustive et ne doivent pas priver l'internaute de procéder aux recherches qui lui semblent nécessaires. Par ailleurs, nos conseils ne remplacent ni ne doivent vous priver de consulter votre professionnel.le de santé pour toute information complémentaire utile conformément aux conditions générales d'utilisation de notre site .

Associé(s) utilement par exemple avec...

A lire aussi...

Bibliographie

1 International Agency forResearch on Cancer, IARC

Monographs on the Evaluation of Carcinogenic Risks to

Humans, vol. 49, Chromium, Nickel and Welding, IARC

Scientific Publications, Lyon, 1990, pp. 257–445.

2 F.W. Sunderman Jr., Nickel, in: M. Anke, M. Ihnat, M.

Stoeppler (Eds.), Elements and their Compounds in the

Environment, Wiley/VCH, Weinheim, in press.

3 D.G. Barceloux, Nickel, Clin. Tox. 37 (1999) 239–258.

4 T.P. Coogan, D.M. Latta, E.T. Snow, M. Costa, Toxicity and

carcinogenicity of nickel compounds, Crit. Rev. Toxicol. 19

(1989) 341–384.

5 E. Denkhaus, K. Salnikow, Nickel essentiality, toxicity, and

carcinogenicity, Crit. Rev. Oncol. Hematol. 42 (2002) 35–56.

6 R.P. Hausinger, Biochemistry of Nickel, Plenum Press, New

York, 1993.

7 E. Nieboer, J.O. Nriagu (Eds.), Nickel and Human Health,

Wiley, New York, 1992.

8 S.W. Ragsdale, Nickel biochemistry, Curr. Opin. Chem. Biol.

2 (1998) 208–215.

9 H. Savolainen, Biochemical and clinical aspects of nickel

toxicity, Rev. Environ. Health 11 (1996) 167–173.

10 F.W. Sunderman Jr., Nickel, in: H.G. Seiler, H. Sigel,

A. Sigel (Eds.), Handbook on Toxicity of Inorganic

Compounds, Marcel Dekker, New York, 1988, pp. 453–468.

11 F.W. Sunderman Jr., Nickel, in: J.B. Sullivan Jr.,

G.R. Krieger (Eds.), Clinical Environmental Health and

Toxic Exposures, Williams and Wilkins, Baltimore, 2001,

pp. 905–910.

12 F.W. Sunderman Jr., A. Aitio, L.M. Morgan, T. Norseth,

Biological monitoring of nickel, Toxicol. Ind. Health 2

(1986) 17–78.

13 S.M. Hopfer, J.V. Linden, M.C. Crisostomo, F.A.

Catalanatto, M. Galen, F.W. Sunderman Jr., Hypernickelemia

in hemodialysis patients, Trace Elem. Med. 2 (1985)

68–72.

14 G.S. Fell, D. Maharaj, Trace metal contamination of albumin

solutions used for plasma exchange, Lancet 2 (1986) 467–

468.

15 C.N. Leach Jr., F.W. Sunderman Jr., Nickel contamination

of human serum albumin solutions, N. Engl. J. Med. 313

(1985) 1232.

16 C.N. Leach Jr., F.W. Sunderman Jr., Hypernickelemia following

coronary arteriography, caused by nickel in the

radiographic contrast medium, Ann. Clin. Lab. Sci. 17 (1987)

137–144.

17 P.M. Gordon, M.I. White, T.R. Scotland, Generalized

sensitivity from an implanted orthopaedic antibiotic minichain

containing nickel, Contact Dermat. 30 (1994) 181–

182.

18 J.J. Hostynek, H.I. Maibach, Nickel and the Skin, CRC

Press, Boca Raton, 2002, pp. 1–249.

19 T. Norseth, M. Piscator, Nickel, in: L. Friberg, G.F.

Nordberg, V.B. Vouk (Eds.), Handbook on the Toxicology

of Metals, Elsevier/North-Holland Biomedical Press,

Amsterdam, 1979, pp. 541–553.

 

20 P. Grandjean, Human exposure to nickel, in: F.W. Sunderman

Jr., (Ed.), Nickel in the Human Environment, vol. 53, IARC

Scientific Publications, Lyon,1984, pp. 469–485.

21 E.W. Baader, Berufkrebs, Neu. Ergeb. Geb. Krebskrankh 1

(1937) 104–128.

22 National Academy of Sciences (NAS) Nickel, Medical and

Biologic Effects of Environmental Pollutants, NAS Press,

Washington, DC, 1975, pp. 1–277.

23 R. Doll, Report of the International Committee on Nickel

Carcinogenesis in Man, Scand. J. Work. Environ. Health 16

(1990) 9–82.

24 T.K. Grimsrud, S.R. Berge, J.I. Martinsen, A. Andersen,

Lung cancer incidence among Norwegian nickel-refinery

workers, 1953–2000, J. Environ. Monit. 5 (2003) 190–197.

25 K.S. Kasprzak, Animal studies, an overview, in: E. Nieboer,

J.O. Nriagu (Eds.), Nickel and Human Health: Current

Perspectives, Wiley, New York, 1992, pp. 387–420.

26 A.R. Oller, M. Costa, G. Oberdörster, Carcinogenicity

assessment of selected nickel compounds, Toxicol. Appl.

Pharmacol. 143 (1997) 152–166.

27 F.W. Sunderman Jr., The current status of nickel carcinogenesis,

Ann. Clin. Lab. Sci. 3 (1973) 157–180.

28 F.W. Sunderman Jr., Carcinogenicity of nickel compounds

in animals, in: F.W. Sunderman Jr., (Ed.), Nickel in the

88 K.S. Kasprzak et al. / Mutation Research 533 (2003) 67–97

Human Environment, vol. 53, IARC Scientific Publications,

Lyon, 1984, pp. 127–142.

29 F.W. Sunderman Jr., L.G. Morgan, A. Andersen, D. Ashley,

F.A. Forouhar, Histopathology of sinonasal and lung cancers

in nickel refinery workers, Ann. Clin. Lab. Sci. 19 (1989)

44–50.

30 K. Hughes, M.E. Meek, R. Newhook, P.K.L. Chan,

Speciation and health risk assessment of metals: evaluation

of effects associated with forms present in the environment,

Regul. Toxicol. Pharmacol. 22 (1995) 213–220.

31 F.W. Sunderman Jr., Carcinogenicity of metal alloys in

orthopedic prostheses: clinical and experimental studies,

Fundam. Appl. Toxicol. 13 (1989) 205–216.

32 J.K. Avery, A. Goldberg, K.S. Kasprzak, L.C. Lucas,

H.D. Millard, J.R. Natiella, R. Rhyne, N.W. Rupp, D.F.

Williams, Local tissue reaction and carcinogenesis (Section

Report), in: B.R. Lang, H.F. Morris, M.E. Razzoog, (Eds.),

Biocompatibility, Toxicity, and Hypersensitivity to Alloy

Systems Used in Dentistry, University of Michigan, Ann

Arbor, 1986, pp. 262–270.

33 D.B. McGregor, R.A. Baan, C. Partensky, J.M. Rice, J.D.

Wilbourn, Evaluation of the carcinogenic risks to humans

associated with surgical implants and other foreign bodies—

a report of an IARC Monographs Programme Meeting, Eur.

J. Cancer 36 (2000) 307–313.

34 J.A. Campbell, Lung tumours in mice and man, Br. Med.

J. 1 (1943) 179–183.

35 L.A. Poirier, J.C. Theiss, L.J. Arnold, M.B. Shimkin,

Inhibition by magnesium and calcium acetates of lead

subacetate- and nickel acetate-induced lung tumors in strain

A mice, Cancer Res. 44 (1984) 1520–1522.

36 K.S. Kasprzak, B.A. Diwan, N. Konishi, M. Misra, J.M.

Rice, Initiation by nickel acetate and promotion by sodium

barbital of renal cortical epithelial tumors in male F344 rats,

Carcinogenesis 11 (1990) 647–652.

37 F. Pott, M. Rippe, M. Roller, M. Csicsaky, M. Rosenbruch,

Carcinogenicity of nickel compounds and nickel alloys in

rats by intraperitoneal injection, in: E. Nieboer, J.O. Nriagu

(Eds.), Nickel and Human Health: Current Perspectives,

Wiley, New York, 1992, pp. 491–502.

38 B.A. Diwan, K.S. Kasprzak, J.M. Rice, Transplacental

carcinogenic effects of nickel(II) acetate in the renal cortex,

Carcinogenesis 13 (1992) 1351–1357.

39 J.P.W. Gilman, Metal carcinogenesis. II. A study on the

carcinogenic activity of cobalt, copper, iron, and nickel

compounds, Cancer Res. 22 (1962) 158–165.

40 H.F. Hildebrand, G. Biserte, Cylindrical laminated bodies

in nickel-subsulphide-induced rhabdomyosarcoma in rabbits,

Eur. J. Cell. Biol. 19 (1979) 276–280.

41 F.W. Sunderman Jr., R.M. Maenza, P.R. Alpass, J.M.

Mitchell, I. Damjanov, P.J. Goldblatt, Carcinogenicity of

nickel subsulfide in Fischer rats and Syrian hamsters after

administration by various routes, Adv. Exp. Med. Biol. 91

(1977) 57–67.

42 S. Yamashiro, J.P. Gilman, T.J. Hulland, H.M. Abandowitz,

Nickel sulphide-induced rhabdomyosarcomata in rats, Acta

Pathol. Jpn. 30 (1980) 9–22.

43 K.S. Kasprzak, P. Gabryel, K. Jarczewska, Carcinogenicity

of nickel(II)hydroxides and nickel(II)sulfate in Wistar

rats and its relation to the in vitro dissolution rates,

Carcinogenesis 4 (1983) 275–279.

44 M. Shibata, K. Izumi, N. Sano, A. Akagi, H. Otsuka,

Induction of soft tissue tumours in F344 rats by

subcutaneous, intramuscular, intra-articular, and retroperitoneal

injection of nickel sulphide (Ni3S2), J. Pathol. 157

(1989) 263–274.

45 C. Onkelinx, J. Becker, F.W. Sunderman Jr., Compartmental

analysis of the metabolism of 63Ni(II) in rats and rabbits,

Res. Commun. Chem. Pathol. Pharmacol. 6 (1973) 663–676.

46 A. Oskarsson, Y. Andersson, H. Tjalve, Fate of nickel

subsulfide during carcinogenesis studied by autoradiography

and X-ray powder diffraction, Cancer Res. 39 (1979) 4175–

4182.

47 N. Sano, M. Shibata, K. Izumi, H. Otsuka, Histopathological

and immunohistochemical studies on nickel sulfide-induced

tumors in F344 rats, Jpn. J. Cancer Res. 79 (1988) 212–221.

48 G.D. Stoner, M.B. Shimkin, M.C. Troxell, T.L. Thompson,

L.S. Terry, Test for carcinogenicity of metallic compounds

by the pulmonary tumor response in strain A mice, Cancer

Res. 36 (1976) 1744–1747.

49 A.V. Saknyn, V.A. Blokhin, Development of malignant

tumors in rats under the influence of nickel-containing

aerosols, Vopr. Onkol. 24 (1978) 44–48.

50 K. Parker, F.W. Sunderman Jr., Distribution of 63Ni in

rabbit tissues following intravenous injection of 63NiCl2,

Res. Commun. Chem. Pathol. Pharmacol. 7 (1974) 755–762.

51 G. Jasmin, J.L. Riopelle, Renal carcinomas and erythrocytosis

in rats following intrarenal injection of nickel

subsulfide, Lab. Invest. 35 (1976) 71–78.

52 G. Jasmin, B. Solymoss, The topical effects of nickel

subsulfide on renal parenchyma, Adv. Exp. Med. Biol. 91

(1977) 69–83.

53 F.W. Sunderman Jr., R.M. Maenza, S.M. Hopfer, J.M.

Mitchell, P.R. Allpass, I. Damjanov, Induction of renal

cancers in rats by intrarenal injection of nickel subsulfide,

J. Environ. Pathol. Toxicol. 2 (1979) 1511–1527.

54 K.S. Kasprzak, B.A. Diwan, J.M. Rice, Iron accelerates

while magnesium inhibits nickel-induced carcinogenesis in

the rat kidney, Toxicology 90 (1994) 129–140.

55 G. Jasmin, B. Solymoss, Polycythemia induced in rats by

intrarenal injection of nickel sulfide, Ni3S2, Proc. Soc. Expl.

Biol. Med. 148 (1975) 774–776.

56 B. Solymoss, G. Jasmin, Studies of the mechanism of

polycythemia induced in ras by Ni3S2, Exp. Hematol. 6

(1978) 43–47.

57 F.W. Sunderman Jr., K.S. McCully, S.M. Hopfer, Association

between erythrocytosis and renal cancers in rats

following intrarenal injection of nickel compounds,

Carcinogenesis 5 (1984) 1511–1517.

58 I. Damjanov, F.W. Sunderman, J.M. Mitchell, P.R. Allpass,

Induction of testicular sarcoma in Fischer rats by

intratesticular injection of nickel subsulfide, Cancer Res. 38

(1978) 268–276.

59 D.M. Albert, J.R. Gonder, J. Papale, J.L. Craft, H.G.

Dohlman, M.C. Reid, F.W. Sunderman Jr., Induction of

K.S. Kasprzak et al. / Mutation Research 533 (2003) 67–97 89

ocular neoplasms in Fischer rats by intraocular injection of

nickel subsulfide, Invest. Ophthalmol. Vis. Sci. 22 (1982)

768–782.

60 M. Okamoto, Induction of ocular tumor by nickel subsulfide

in the Japanese common newt, Cynops pyrrhogaster, Cancer

Res. 47 (1987) 5213–5217.

61 F.W. Sunderman Jr., A. Donnelly, B. West, J.F. Kincaid,

Nickel poisoning. IX. Carcinogenesis in rats exposed to

nickel carbonyl, Arch. Ind. Health 20 (1959) 36–41.

62 A.D. Ottolenghi, J.K. Haseman, W.W. Payne, H.L. Falk,

H.N. MacFarland, Inhalation studies of nickel sulfide in

pulmonary carcinogenesis of rats, J. Natl. Cancer Inst. 54

(1975) 1165–1172.

63 T. Yarita, P. Nettesheim, Carcinogenicity of nickel subsulfide

for respiratory tract mucosa, Cancer Res. 38 (1978) 3140–

3145.

64 J.K. Dunnick, M.R. Elwell, A.E. Radovsky, J.M. Benson,

F.F. Hahn, K.J. Nikula, E.B. Barr, C.H. Hobbs, Comparative

carcinogenic effects of nickel subsulfide, nickel oxide, or

nickel sulfate hexahydrate chronic exposures in the lung,

Cancer Res. 55 (1955) 5251–5256.

65 NTP Study, Toxicology and Carcinogenesis Studies of

Nickel Oxide 1996 (CAS No. 10101-97-0 CAS No.

1313-99-1 CAS No. 12035-72-2) in F344/N Rats and

B6C3F1 Mice (Inhalation Studies), US DHHS, Atlanta, GA.

66 R.M. Maenza, A.M. Pradhan, F.W. Sunderman Jr., Rapid

induction of sarcomas in rats by combination of nickel

sulfide and 3,4-benzpyrene, Cancer Res. 31 (1971) 2067–

2071.

67 K.S. Kasprzak, L. Marchow, J. Breborowicz, Pathological

reactions in rat lungs following intratracheal injection of

nickel subsulfide and 3,4-benzpyrene, Res. Commun. Chem.

Pathol. Pharmacol. 6 (1973) 237–245.

68 F.W. Sunderman Jr., K.S. Kasprzak, T.J. Lau, P.O.

Minghetti, R.M. Maenza, N. Becker, C. Onkelinx, P.J.

Goldblatt, Effect of manganese on carcinogenicity and

metabolism of nickel subsulfide, Cancer Res. 36 (1976)

1790–1800.

69 F.W. Sunderman Jr., K.S. McCully, Effects of manganese

compounds on carcinogenicity of nickel subsulfide in rats,

Carcinogenesis 4 (1983) 461–465.

70 K.S. Kasprzak, R.V. Quander, L.A. Poirier, Effects

of calcium and magnesium salts on nickel subsulfide

carcinogenicity in Fischer rats, Carcinogenesis 6 (1985)

1161–1166.

71 K.S. Kasprzak, J.M. Ward, L.A. Poirier, D.A. Reichardt,

A.C. Denn III, C.W. Reynolds, Nickel–magnesium interactions

in carcinogenesis: dose–effects and involvement of

natural killer cells, Carcinogenesis 8 (1987) 1005–1011.

72 K.S. Kasprzak, R.M. Kovatch, L.A. Poirier, Inhibitory effect

of zinc on nickel subsulfide carcinogenesis in Fischer rats,

Toxicology 52 (1988) 253–262.

73 K.S. Kasprzak, B.A. Diwan, J.M. Rice, Iron accelerates

while magnesium inhibits nickel-induced carcinogenesis in

the rat kidney, Toxicology 90 (1994) 129–140.

74 K.S. Kasprzak, R.E. Rodriguez, Inhibitory effects of zinc,

magnesium, and iron on nickel subsulfide carcinogenesis

in rat skeletal muscle, in: E. Nieboer, J.O. Nriagu (Eds.),

Nickel in Human Health: Current Perspectives, Wiley, New

York, 1992, pp. 545–559.

75 F.W. Sunderman Jr., Organ and species specificity in nickel

subsulfide carcinogenesis, Basic Life Sci. 24 (1983) 107–

127.

76 R.E. Rodriguez, M. Misra, B.A. Diwan, C.W. Riggs, K.S.

Kasprzak, Relative susceptibilities of C57BL/6, (C57BL/6× C3H/He)F1, and C3H/He mice to acute toxicity and

carcinogenicity of nickel subsulfide, Toxicology 107 (1996)

131–140.

77 M.R. Daniel, Strain differences in the response of rats to

the injection of nickel sulphide, Br. J. Cancer 20 (1966)

886–895.

78 R.E. Rodriguez, M. Misra, S.L. North, K.S. Kasprzak,

Nickel-induced lipid peroxidation in the liver of different

strains of mice and its relation to nickel effects on antioxidant

systems, Toxicol. Lett. 57 (1991) 269–281.

79 G.L. Fisher, C.E. Chrisp, D.A. McNeill, Lifetime effects of

intratracheally instilled nickel subsulfide on B6C3F1 mice,

Environ. Res. 40 (1986) 313–320.

80 F.W. Sunderman Jr., Recent research on nickel carcinogenesis,

Environ. Health Perspect. 40 (1981) 131–141.

81 T. Eitinger, M.A. Mandrand-Berthelot, Nickel transport

systems in microorganisms, Arch. Microbiol. 173 (2000)

1–9.

82 P. Pikalek, J. Necasek, The mutagenic activity of nickel in

Corynebacterium sp., Folia Microbiol. (Praha) 28 (1983)

17–21.

83 J.A. DiPaolo, B.C. Casto, Quantitative studies of in vitro

morphological transformation of Syrian hamster cells by

inorganic metal salts, Cancer Res. 39 (1979) 1008–1013.

84 K.A. Biedermann, J.T. Landolph, Induction of anchorage

independence in human diploid foreskin fibroblasts by

carcinogenic metal salts, Cancer Res. 47 (1987) 3815–3823.

85 S.R. Patierno, L.A. Dirscherl, J. Xu, Transformation of

rat tracheal epithelial cells to immortal growth variants by

particulate and soluble nickel compounds, Mutat. Res. 300

(1993) 179–193.

86 M. Costa, Mechanisms of nickel genotoxicity and

carcinogenicity, in: L.W. Chang (Ed.), Toxicology of Metals,

CRC Press, Boca Raton, 1996, pp. 245–251.

87 G.A. Kerckaert, R.A. LeBoeuf, R.J. Isfort, Use of the Syrian

hamster embryo cell transformation assay for determining

the carcinogenic potential of heavy metal compounds,

Fundam. Appl. Toxicol. 34 (1996) 67–72.

88 M. Costa, J.S. Nye, F.W. Sunderman Jr., P.R. Allpass, B.

Gondos, Induction of sarcomas in nude mice by implantation

of Syrian hamster fetal cells exposed in vitro to nickel

subsulfide, Cancer Res. 39 (1979) 3591–3597.

89 D.A. Trott, A.P. Cuthbert, R.W. Overell, I. Russo, R.F.

Newbold, Mechanisms involved in the immortalization

of mammalian cells by ionizing radiation and chemical

carcinogens, Carcinogenesis 16 (1995) 193–204.

90 K. Hansen, R.M. Stern, In vitro toxicity and transformation

potency of nickel compounds, Environ. Health Perspect. 51

(1983) 223–226.

90 K.S. Kasprzak et al. / Mutation Research 533 (2003) 67–97

91 H.J. Saxholm, A. Reith, A. Brogger, Oncogenic

transformation and cell lysis in C3H/10T 1/2 cells and

increased sister chromatid exchange in human lymphocytes

by nickel subsulfide, Cancer Res. 41 (1981) 4136–4139.

92 G. Tveito, I-L. Hansteen, H. Dalen, A. Haugen, Immortalization

of normal human kidney epithelial cells by

nickel(II), Cancer Res. 49 (1989) 1829–1835.

93 A. Haugen, D. Ryberg, I-L. Hansteen, H. Dalen, Transformation

of human kidney epithelial cells to tumorigenicity

by nickel(II) and v-Ha-ras oncogene, Biol. Trace Element

Res. 21 (1989) 451–458.

94 E. Rivedal, T. Sanner, Metal salts as promoters of in

vitro morphological transformation of hamster embryo cells

initiated by benzoapyrene, Cancer Res. 41 (1981) 2950–

2953.

95 H. Miki, K.S. Kasprzak, S. Kenney, U.I. Heine, Inhibition

of intercellular communication by nickel(II): antagonistic

effect of magnesium, Carcinogenesis 8 (1987) 1757–1760.

96 E.C. Foulkes, D.M. McMullen, On the mechanism of nickel

absorption in the rat jejunum, Toxicology 38 (1986) 35–42.

97 T. Refvik, T. Andreassen, Surface binding and uptake of

nickel(II) in human epithelial kidney cells: modulation by

ionomycin, Carcinogenesis 16 (1995) 1107–1112.

98 G. Zaroogian, P. Yevich, S. Anderson, Effect of selected

inhibitors on cadmium, nickel, and benzoapyrene uptake

into brown cells of Mercenaria mercenaria, Marine Environ.

Res. 35 (1993) 41–45.

99 F.J. Azula, R. Alonso, A. Marino, M. Trueba, J.M.

Macarulla, Ni2+ impairs thrombin-induced signal transduction

by acting on the agonist and/or receptor in human

platelets, Am. J. Physiol. 265 (1993) C1681–C1688.

100 J. Tallkvist, A.M. Wing, H. Tjalve, Enhanced intestinal

nickel absorption in iron-deficient rats, Pharmacol. Toxicol.

75 (1994) 244–249.

101 S.G. Schafer, W. Forth, The influence of tin, nickel, and

cadmium on the intestinal absorption of iron, Ecotoxicol.

Environ. Safety 7 (1983) 87–95.

102 M. Muller-Fassbender, B. Elsenhans, A.T. McKie, K.

Schumann, Different behaviour of 63Ni and 59Fe during

absorption in iron-deficient and iron-adequate jejunal rat

segments ex vivo, Toxicology 185 (2003) 141–153.

103 H. Gunshin, B. Mackenzie, U.V. Berger, Y. Gunshin, M.R.

Romero, W.F. Boron, S. Nussberger, J.L. Gollan, M.A.

Hediger, Cloning and characterization of a mammalian

proton-coupled metal-ion transporter, Nature 388 (1997)

482–488.

104 J. Tallkvist, H. Tjalve, Transport of nickel across monolayers

of human intestinal Caco-2 cells, Toxicol. Appl. Pharmacol.

151 (1998) 117–122.

105 M. Knopfel, G. Schulthess, F. Funk, H. Hauser, Characterization

of an integral protein of the brush border

membrane mediating the transport of divalent metal ions,

Biophys. J. 79 (2000) 874–884.

106 A.J. Ghio, J.H. Richards, K.L. Dittrich, J.M. Samet, Metal

storage and transport proteins increase after exposure of the

rat lung to an air pollution particles, Toxicol. Pathol. 26

(1998) 388–394.

107 M. Costa, J. Simmons-Hansen, C.W.M. Bedrossian, J.

Bonura, R.M. Caprioli, Phagocytosis, cellular distribution,

and carcinogenic activity of particulate nickel compounds

in tissue culture, Cancer Res. 41 (1981) 2868–2876.

108 J.D. Heck, M. Costa, Surface reduction of amorphous

NiS particles potentiates their phagocytosis and subsequent

induction of morphological transformation in Syrian hamster

embryo cells, Cancer Lett. 15 (1982) 19–26.

109 K. Kuehn, C.B. Fraser, F.W. Sunderman Jr., Phagocytosis of

particulate nickel compounds by rat peritoneal macrophages

in vitro, Carcinogenesis 3 (1982) 321–326.

110 M. Costa, M.P. Abbracchio, J. Simmons-Hansen, Factors

influencing the phagocytosis, neoplastic transformation, and

cytotoxicity of particulate nickel compounds in tissue culture

systems, Toxicol. Appl. Pharmacol. 60 (1981) 313–323.

111 M. Costa, H.H. Mollenhauer, Carcinogenic activity of

particulate nickel compounds is proportional to their cellular

uptake, Science 209 (1980) 515–517.

112 R.M. Evans, P.J. Davies, M. Costa, Video time-lapse

microscopy of phagocytosis and intracellular fate of

crystalline nickel sulfide particles in cultured mammalian

cells, Cancer Res. 42 (1982) 2729–2735.

113 G.G. Fletcher, F.E. Rosetto, J.D. Turnbull, E. Nieboer,

Toxicity, uptake, and mutagenicity of particulate and soluble

nickel compounds, Environ. Health Perspect. 102 (Suppl. 3)

(1994) 69–79.

114 K.S. Kasprzak, F.W. Sunderman Jr., Mechanisms of

dissolution of nickel subsulfide in rats serum, Res. Commun.

Chem. Pathol. Pharmacol. 16 (1977) 95–108.

115 K. Kuehn, F.W. Sunderman Jr., Dissolution half-times of

nickel compounds in water, rat serum, and renal cytosol, J.

Inorg. Biochem. 17 (1982) 29–39.

116 A. Longstaff, A.I.T. Walker, R. Jackh, Nickel oxide, potential

carcinogenicity—a review and further evidence, in: F.W.

Sunderman (Ed.), Nickel in the Human Environment, vol.

53, IARC Scientific Publications, Lyon, 1984, pp. 235–244.

117 P. Sen, K. Conway, M. Costa, Comparison of the localization

of chromosome damage induced by calcium chromate and

nickel compounds, Cancer Res. 47 (1987) 2142–2147.

118 K. Conway, M. Costa, Nonrandom chromosomal alterations

in nickel-transformed Chinese hamster embryo cells, Cancer

Res. 49 (1989) 6032–6038.

119 P. Sen, M. Costa, Incidence and localization of sister

chromatid exchanges induced by nickel and chromium

compounds, Cancer Res. 7 (1985) 1527–1533.

120 R.K. Sahu, S.P. Katsifis, P.L. Kinney, N.T. Christie, Effects

of nickel sulfate, lead sulfate, and sodium arsenite alone and

with UV light on sister chromatid exchanges in cultured

human lymphocytes, J. Mol. Toxicol. 2 (1989) 129–136.

121 F.Z. Arrouijal, H.F. Hildebrand, H. Vophi, D. Marzin,

Genotoxic activity of nickel subsulphide alpha-Ni3S2,

Mutagenesis 5 (1990) 583–589.

122 S.R. Patierno, M. Sugiyama, J.P. Basilion, M. Costa,

Preferential DNA–protein crosslinking by NiCl2 in

magnesium-insoluble regions of fractionated Chinese

hamster ovary cell chromatin, Cancer Res. 45 (1985) 5787–

5794.

K.S. Kasprzak et al. / Mutation Research 533 (2003) 67–97 91

123 K.S. Kasprzak, The role of oxidative damage in metal

carcinogenicity, Chem. Res. Toxicol. 4 (1991) 604–615.

124 S. Zienolddiny, D. Ryberg, A. Haugen, Induction of

microsatellite mutations by oxidative agents in human lung

cancer cell lines, Carcinogenesis (2000) 1521–1526.

125 S.M. Chiocca, D.A. Sterner, N.W. Biggart, E.C. Murphy

Jr., Nickel mutagenesis: alteration of the MuSVts110

thermosensitive splicing phenotype by a nickel-induced

duplication of the 3_ splice site, Mol. Carcinog. 4 (1991)

61–71.

126 F.E. Rosetto, J.D. Turnbull, E. Nieboer, Characterization of

nickel-induced mutations, Sci. Total Environ. 148 (1994)

201–206.

127 K.G. Higinbotham, J.M. Rice, B.A. Diwan, K.S. Kasprzak,

C.D. Reed, A.O. Perantoni, GGT to GTT transversions in

codon 12 of the K-ras oncogene in rat renal sarcomas

induced with nickel subsulfide or nickel subsulfide/iron are

consistent with oxidative damage to DNA, Cancer Res. 52

(1992) 4747–4751.

128 L.C. Harty, D.G. Guinee Jr., W.D. Travis, W.P. Bennett,

J. Jett, T.V. Coby, H. Tazelaar, V. Trastek, P. Pairolero,

L.A. Liotta, C.C. Harris, N.E. Caporaso, p53 mutations and

occupational exposures in a surgical series of lung cancers,

Cancer Epidemiol. Biomark. Prev. 5 (1996) 997–1003.

129 N.W. Biggart, M. Costa, Assessment of the uptake and

mutagenicity of nickel chloride in Salmonella tester strains,

Mutat. Res. 175 (1986) 209–215.

130 B. Kargacin, C.B. Klein, M. Costa, Mutagenic responses of

nickel oxides and nickel sulfides in Chinese hamster V79

cell lines as the xanthine-guanine phosphoribosyl transferase

locus, Mutat. Res. 300 (1993) 63–72.

131 Y-W. Lee, C.B. Klein, B. Kargacin, K. Salnikow, J.

Kitahara, K. Dowjat, A. Zhitkovich, N.T. Christie, M. Costa,

Carcinogenic nickel silences gene expression by chromatin

condensation and DNA methylation: a new model for

epigenetic carcinogens, Mol. Cell. Biol. 15 (1995) 2547–

2557.

132 R. Rodriguez-Arnaiz, P. Ramos, Mutagenicity of nickel

sulpate in Drosophila melanogaster, Mutat. Res. 170 (1986)

115–117.

133 J.S. Dubins, J.M. LaVelle, Nickel(II) genotoxicity: potentiation

of mutagenesis of simple alkylating agents, Mutat.

Res. 162 (1986) 187–199.

134 C. Mayer, R.G. Klein, H. Wesch, P. Schmezer, Nickel

subsulfide is genotoxic in vitro but shows no mutagenic

potential in respiratory tract tissues of Big Blue rats and

Muta Mouse mice in vivo after inhalation, Mutat Res. 420

(1998) 85–98.

135 N.T. Christie, D.M. Tummolo, C.B. Klein, T.G. Rossman,

Role of Ni(II) in mutation, in: E. Nieboer, J.O. Nriagu (Eds.),

Nickel and Human Health: Current Perspectives, Wiley, New

York, 1992, pp. 305–317.

136 N.W. Biggart, G.E. Gallick, E.C. Murphy Jr., Nickelinduced

heritable alterations in retroviral transforming gene

expression, J. Virol. 61 (1987) 2378–2388.

137 L. Broday, W. Peng, M.H. Kuo, K. Salnikow, M. Zoroddu,

M. Costa, Nickel compounds are novel inhibitors of histone

H4 acetylation, Cancer Res. 60 (2000) 238–241.

138 F.W. Sunderman Jr., S.M. Hopfer, M. C Reid, S. K Shen,

C.B. Kevorkian, Erythropoietin-mediated erythrocytosis in

rodents after intrarenal injection of nickel subsulfide, Yale

J. Biol. Med. 55 (1982) 123–136.

139 F.W. Sunderman Jr., K.S. McCully, S.M. Hopfer, Association

between erythrocytosis and renal cancers in

rats following intrarenal injection of nickel compounds,

Carcinogenesis 5 (1984) 1511–1517.

140 G.L. Semenza, G.L. Wang, A nuclear factor induced

by hypoxia via de novo protein synthesis binds to the

human erythropoietin gene enhancer at a site required for

transcriptional activation, Mol. Cell. Biol. 12 (1992) 5447–

5454.

141 K.K. Graven, R.J. McDonald, H.W. Farber, Hypoxia

regulation of endothelial glyceraldehyde-3-phosphate dehydrogenase,

Am. J. Physiol. 43 (1998) 347–355.

142 K. Salnikow, M.W. Blagosklonny, H. Ryan, R. Johnson,

M. Costa, Carcinogenic nickel induces genes involved in

hypoxic stress, Cancer Res. 60 (2000) 38–41.

143 A. Namiki, E. Brogi, M. Kearney, E.A. Kim, T. Wu, T.

Couffinhal, L. Varticovski, J.M. Isner, Hypoxia induces

vascular endothelial growth factor in cultured human

endothelial cells, J. Biol. Chem. 270 (1995) 31189–31195.

144 D. Zhou, K. Salnikow, M. Costa, Cap43, a novel gene

specifically induced by Ni2+ compounds, Cancer Res. 58

(1998) 2182–2189.

145 K. Salnikow, W.G. An, G. Melillo, M.V. Blagosklonny,

M. Costa, Nickel-induced transformation shifts the

balance between HIF-1_ and p53 transcription factors,

Carcinogenesis 20 (1999) 1819–1823.

146 G.L. Semenza, Expression of hypoxia-inducible factor 1:

mechanisms and consequences, Biochem. Pharmacol. 59

(2000) 47–53.

147 G.L. Semenza, HIF-1, O2, and the 3 PHDs: how animal

cells signal hypoxia to the nucleus, Cell 107 (2001) 1–3.

148 P. Carmeliet, Y. Dor, J.M. Herbert, D. Fukumura, K.

Brusselmans, M. Dewerchin, M. Neeman, F. Bono, R.

Abramovitch, P. Maxwell, C.J. Koch, P. Ratcliffe, L. Moons,

R.K. Jain, D. Collen, E. Keshet, Role of HIF-1_ in

hypoxia-mediated apoptosis, cell proliferation and tumour

angiogenesis, Nature 394 (1998) 485–490.

149 J. Folkman, Tumor angiogenesis: therapeutic implications,

N. Engl. J. Med. 285 (1971) 1182–1186.

150 G.L. Semenza, P.H. Roth, H.-M. Fang, G.L. Wang, Transcriptional

regulation of genes encoding glycolitic enzymes

by hypoxia-inducible factor 1, J. Biol. Chem. 269 (1994)

23757–23763.

151 A. Rolfs, I. Kvietikova, M. Gassmann, R.H. Wenger,

Oxygen-regulated transferrin expression is mediated by

hypoxia-inducible factor-1, J. Biol. Chem. 272 (1997)

20055–20062.

152 G. Melillo, T. Musso, A. Sica, L.S. Taylor, G.W. Cox, L.

Varesio, A hypoxia-responsive element mediates a novel

pathway of activation of the inducible nitric oxide synthase

promoter, J. Exp. Med. 182 (1995) 1683–1693.

153 M. Garayoa, A. Martinez, S. Lee, R. Pio, W.G. An,

L. Neckers, J. Trepel, L.M. Montuenga, H. Ryan, R.

92 K.S. Kasprzak et al. / Mutation Research 533 (2003) 67–97

Johnson, M. Gassmann, F. Cuttitta, Hypoxia-inducible

factor-1 (HIF-1) up-regulates adrenomedullin expression in

human tumor cell lines during oxygen deprivation: a possible

promotion mechanism of carcinogenesis, Mol. Endocrinol.

14 (2000) 848–862.

154 K. Salnikow, T. Davidson, M. Costa, The role of hypoxiainducible

signaling pathway in nickel carcinogenesis,

Environ. Health Perspect. 110 (Suppl. 5) (2002) 831–834.

155 K. Salnikow, T. Davidson, T. Kluz, H. Chen, D. Zhou, M.

Costa, GeneChip analysis of signaling pathways effected by

nickel, J. Environ. Monitor. 5 (2003) 1–5.

156 K. Salnikow, T. Davidson, Q. Zhang, L.C. Chen, W. Su, M.

Costa, The involvement of hypoxia-inducible transcription

factor-1-dependent pathway in nickel carcinogenesis, Cancer

Res. 63 (2003) 3524–3530.

157 K. Salnikow, W. Su, M.V. Blagosklonny, M. Costa,

Carcinogenic metals induce hypoxia-inducible factorstimulated

transcription by reactive oxygen speciesindependent

mechanism, Cancer Res. 60 (2000) 3375–3378.

158 C.H. Sutter, E. Laughner, G.L. Semenza, Hypoxia-inducible

factor 1_ protein expression is controlled by oxygenregulated

ubiqitination that is disrupted by deletions and

missense mutations, Proc. Natl. Acad. Sci. U.S.A. 97 (2000)

4748–4753.

159 U.R. Jewell, I. Kvietikova, A. Scheid, C. Bauer, R.H.

Wenger, M. Gassmann, Induction of HIF-1alpha in response

to hypoxia is instantaneous, FASEB J. 15 (2001) 1312–1314.

160 M. Ivan, K. Kondo, H. Yang, W. Kim, J. Valiando, M.

Ohh, A. Salic, J.M. Asara, W.S. Lane, W.G.J. Kaelin,

HIFalpha targeted for VHL-mediated destruction by proline

hydroxylation: implications for O2 sensing, Science 292

(2001) 464–468.

161 P. Jaakkola, D.R. Mole, Y.M. Tian, M.I. Wilson, J.

Gielbert, S.J. Gaskell, A. Kriegsheim, H.F. Hebestreit,

M. Mukherji, C.J. Schofield, P.H. Maxwell, C.W. Pugh,

P.J. Ratcliffe, Targeting of HIF-alpha to the von

Hippel–Lindau ubiquitylation complex by O2-regulated

prolyl hydroxylation, Science 292 (2001) 468–472.

162 F. Yu, S.B. White, Q. Zhao, F.S. Lee, HIF-1_ binding to

VHL is regulated by stimulus-sensitive proline hydroxylation,

Proc. Natl. Acad. Sci. U.S.A. 98 (2001) 9630–9635.

163 M. Ohh, C.W. Park, M. Ivan, M.A. Hoffman, T.-Y. Kim, L.E.

Huang, N. Pavletich, V. Chau, W.G. Kaelin, Ubiquination

of hypoxia-inducible factor requires direct binding to the

beta-domain of the von Hippel–Lindau protein, Nat. Cell

Biol. 2 (2000) 423–427.

164 L.A. McNeill, K.S. Hewitson, T.D. Claridge, J.F. Seibel,

L.E. Horsfall, C.J. Schofield, Hypoxia-inducible factor

asparaginyl hydroxylase (FIH-1) catalyses hydroxylation at

the beta-carbon of asparagine-803, Biochem J. 367 (2002)

571–575.

165 D. Lando, D.J. Peet, D.A. Whelan, J.J. Gorman, M.L.

Whitelaw, Asparagine hydroxylation of the HIF transactivation

domain a hypoxic switch, Science 295 (2002)

858–861.

166 K. Salnikow, S. Cosentino, C. Klein, M. Costa, Loss

of thrombospondin transcriptional activity in nickeltransformed

cells, Mol. Cell. Biol. 14 (1994) 851–858.

167 K. Salnikow, S. Wang, M. Costa, Induction of activating

transcription factor I by nickel and its role as a negative

regulator of thrombospondin I gene expression, Cancer Res.

57 (1997) 5060–5066.

168 A.J. Shaywitz, M.E. Greenberg, CREB: a stimulus-induced

transcription factor activated by a diverse array of

extracellular signals, Annu. Rev. Biochem. 68 (1999) 821–

861.

169 M. Goebeler, G. Meinardus-Hager, J. Roth, S. Goerdt, C.

Sorg, Nickel chloride and cobalt chloride, two common

contact sensitizers, directly induce expression of intercellular

adhesion molecule-1 (ICAM-1), vascular cell adhesion

molecule-1 (VCAM-1), and endothelial leukocyte adhesion

molecule (ELAM-1) by endothelial cells, J. Invest. Dermatol.

100 (1993) 759–765.

170 M. Goebeler, J. Roth, E.B. Brocker, C. Sorg, K. Schulze-

Osthoff, Activation of nuclear factor-kappa B and gene

expression in human endothelial cells by the common

haptens nickel and cobalt, J. Immunol. 155 (1995) 2459–

2467.

171 T. Hernandez-Boussard, P. Rodriguez-Tome, R. Montesano,

P. Hainaut, IARC p53 mutation database: a relational

database to compile and analyze p53 mutations in human

tumors and cell lines, Hum. Mutat. 14 (1999) 1–8.

172 L. Maehle, R.A. Metcalf, D. Ryberg, W.P. Bennett,

C.C. Harris, A. Haugen, Altered p53 gene structure and

expression in human epithelial cells after exposure to nickel,

Cancer Res. 52 (1992) 218–221.

173 C.M. Weghorst, K.H. Dragnev, G.S. Buzard, K.L. Thorne,

G.F. Vandeborne, K.A. Vincent, J.M. Rice, Low incidence of

point mutations detected in the p53 tumor suppressor gene

from chemically induced rat renal mesenchymal tumors,

Cancer Res. 154 (1994) 215–219.

174 Y-H. Shiao, S-H. Lee, K.S. Kasprzak, Cell cycle arrest,

apoptosis and p53 expression in nickel (II) acetate-treated

Chinese hamster ovary cells, Carcinogenesis 19 (1998)

1203–1207.

175 W.G. An, M. Kanekal, M.C. Simon, E. Maltepe, M.V.

Blagosklonny, L.M. Neckers, Stabilization of wild-type p53

by hypoxia-inducible factor 1alpha, Nature 392 (1998) 405–

408.

176 W.H. Lee, R. Bookstein, E.Y. Lee, Studies on the human

retinoblastoma susceptibility gene, J. Cell. Biochem. 38

(1988) 213–227.

177 T. Kouzarides, Transcriptional control by the retinoblastoma

protein, Semin. Cancer Biol. 6 (1995) 91–98.

178 X. Lin, W.K. Dowjat, M. Costa, Nickel-induced transformation

of human cells causes loss of the phosphorylation

of the retinoblastoma protein, Cancer Res. 54 (1994) 2751–

2754.

179 A.S. Rani, D. Qu, M.K. Sidhu, F. Panagakos, V. Shah,

K.M. Klein, N. Brown, S. Pathak, S. Kumar, Transformation

of immortal, non-tumorigenic osteoblast-like

human osteosarcoma cells to the tumorigenic phenotype by

nickel sulfate, Carcinogenesis 14 (1993) 947–953.

180 X. Lin, M. Costa, Transformation of human osteoblasts to

anchorage-independent growth by insoluble nickel particles,

Environ. Health Perspect. 102 (Suppl. 3) (1994) 289–292.

K.S. Kasprzak et al. / Mutation Research 533 (2003) 67–97 93

181 A.C. Miller, W.F. Blakely, D. Livengood, T. Whittaker,

J. Xu, J.W. Ejnik, M.M. Hamilton, E. Parlette, T.S.

John, H.M. Gerstenberg, H. Hsu, Transformation of human

osteoblast cells to the tumorigenic phenotype by depleted

uranium-uranyl chloride, Environ. Health Perspect. 106

(1998) 465–471.

182 F. Trapasso, A. Krakowiak, R. Cesari, J. Arkles, S.

Yendamuri, H. Ishii, A. Vecchione, T. Kuroki, P.

Bieganowski, H.C. Pace, K. Huebner, C.M. Croce, C.

Brenner, Designed FHIT alleles establish that Fhit-induced

apoptosis in cancer cells is limited by substrate binding,

Proc. Natl. Acad. Sci. U.S.A. 100 (2003) 1592–1597.

183 R. Kowara, A. Karaczyn, M.J. Fivash, K.S. Kasprzak, In

vitro inhibition of the enzymatic activity of tumor suppressor

FHIT gene product by carcinogenic transition metals, Chem.

Res. Toxicol. 15 (2002) 319–325.

184 R. Kowara, K. Salnikow, B.A. Diwan, R.M. Bare, M.P.

Waalkes, K.S. Kasprzak, Reduced Fhit protein expression in

nickel-transformed mouse cells and in nickel-induced murine

sarcomas, Mol. Cell. Biochem., in press.

185 S.H. Lee, Y.-H. Shiao, S. Plisov, K.S. Kasprzak, Nickel(II)

acetate-treated Chinese hamster ovary cells differentially

express vimentin, hSNF2H homologue, and H ferritin,

Biochem. Biophys. Res. Commun. 258 (1999) 592–595.

186 G. Lumb, F.W. Sunderman Sr., The mechanism of malignant

tumor induction by nickel subsulfide, Ann. Clin. Lab. Sci.

18 (1988) 353–366.

187 L.G. Burns, C.L. Peterson, Protein complexes for remodeling

chromatin, Biochem. Biophys. Acta 1350 (1997) 159–168.

188 R.Y.S. Cheng, A. Zhao, W.G. Alvord, D. Powell, R.M. Bare,

A. Masuda, T. Takahashi, L.M. Anderson, K.S. Kasprzak,

Gene expression dose–response changes in microarrays

after exposure of human peripheral lung epithelial cells to

nickel(II), Toxicol. Appl. Pharmacol. 191 (2003) 22–39.

189 S.A. McDowell, K. Gammon, C.J. Bachurski, J.S. Wiesdt,

J.E. Leikauf, D.R. Prows, G.D. Leikauf, Differential gene

expression in the initiation and progression of nickel-induced

acute lung injury, Am. J. Respir. Cell Mol. Biol. 23 (2000)

466–474.

190 M.A. Sirover, L.A. Loeb, Infidelity of DNA synthesis

in vitro: screening for potential metal mutagens and

carcinogens, Science 194 (1976) 1434–1436.

191 A. Hartwig, L.H.F. Mullenders, R. Schlepegrell, U. Kasten,

D. Beyersmann, Nickel(II) interferes with the incision step

in nucleotide excision repair in mammalian cells, Cancer 54

(1994) 4045–4051.

192 A. Hartwig, Carcinogenicity of metal compounds: possible

role of DNA repair inhibition, Toxicol. Lett. 28 (1998) 102–

103.

193 F. Iwitzki, R. Schlepegrell, U. Eichhorn, B. Kaina, D.

Beyersmann, A. Hartwig, Nickel(II) inhibits the repair of

O6-methylguanine in mammalian cells, Arch. Toxicol. 72

(1998) 681–689.

194 T. Schwerdtle, A. Seidel, A. Hartwig, Effect of soluble and

particulate nickel compounds on the formation and repair

of stable benzoapyrene DNA adducts in human lung cells,

Carcinogenesis 23 (2002) 47–53.

195 A. Hartwig, M. Asmuss, H. Blessing, S. Hoffmann, G.

Jahnke, S. Khandelwal, A. Pelzer, A. Burkle, Interference

by toxic metal ions with zinc-dependent proteins involved

in maintaining genomic sttability, Food Chem. Toxicol. 40

(2002) 1179–1184.

196 W. Bal, T. Schwerdtle, A. Hartwig, Mechanism of nickel

assault on the zinc finger of DNA repair protein XPA, Chem.

Res. Toxicol. 16 (2003) 242–248.

197 A. Hartwig, M. Asmuss, I. Ehleben, U. Herzer, D. Kostelac,

A. Pelzer, T. Schwerdtle, A. Burkle, Interference by toxic

metal ions with DNA repair processes and cell cycle

control: molecular mechanisms, Environ. Health Perspect.

110 (Suppl. 5) (2002) 797–799.

198 K.S. Kasprzak, K. Bialkowski, Inhibition of antimutagenic

enzymes, 8-oxo-dGTPases, J. Inorg. Biochem. 79 (2000)

231–236.

199 T. Pozzan, R. Rizzuto, P. Volpe, J. Meldolesi, Molecular and

cellular physiology of intracellular calcium stores, Physiol.

Rev. 74 (1994) 595–636.

200 L.B. Rosen, D.D. Ginty, M.E. Greenberg, Calcium regulation

of gene expression, Adv. Second Messenger Phosphoprotein

Res. 30 (1995) 225–253.

201 P. Nicotera, S. Orrenius, The role of calcium in apoptosis,

Cell Calcium 23 (1988) 173–180.

202 K.S. Kasprzak, M.P. Waalkes, The role of calcium,

magnesium, and zinc in carcinogenesis, in: L.A. Poirier,

P.M. Newberne, M.W. Pariza, (Eds.), Essential Nutrients

in Carcinogenesis, Plenum Press, New York, 1986, pp.

497–515.

203 S.H.H. Swierenga, J.F. Whitfield, D.J. Gillan, Alteration by

malignant transformation of the calcium requirements for

cell proliferation in vitro, J. Natl. Cancer Inst. 57 (1976)

125–129.

204 S.H.H. Swierenga, J.F. Whitfield, A.L. Boynton, Age-related

and carcinogen-induced alterations of the extracellular

growth factor requirements for cell proliferation in vitro, J.

Cell. Physiol. 94 (1978) 171–180.

205 K. Salnikow, T. Kluz, M. Costa, Role of Ca2+ in

the regulation of nickel-inducible Cap43 gene expression,

Toxicol. Appl. Pharmacol. 160 (1999) 127–132.

206 T. Funakoshi, T. Inoue, H. Shimada, S. Kojima, The

mechanism of nickel uptake by rat primary hepatocyte

cultures: role of calcium channels, Toxicology 124 (1997)

21–26.

207 G.W. Zamponi, E. Bourinet, T.P. Snutch, Nickel block

of a family of neuronal calcium channels: subtype- and

subunit-dependent action at multiple sites, J. Membrane Biol.

151 (1996) 77–90.

208 J.B. Smith, S.D. Dwyer, L. Smith, Cadmium evokes

inositol polyphosphate formation and calcium mobilization.

Evidence for a cell surface receptor that cadmium stimulates

and zinc antagonizes, J. Biol. Chem. 264 (1989) 7115–7118.

209 J. Sainte-Marie, V. Lafont, E.I. Pecheur, J. Favero, J.R.

Philipot, A. Bienvenue, Transferrin receptor functions as

a signal-transduction molecule for its own recycling via

increases in the internal Ca2+ concentration, Eur. J.

Biochem. 250 (1997) 689–697.

94 K.S. Kasprzak et al. / Mutation Research 533 (2003) 67–97

210 J.D. Glennon, B. Sarkar, Nickel(II) transport in human blood

serum: studies of nickel(II)-binding human albumin and to

native-sequence peptide, and ternary complex formation with

L-histidine, Biochem. J. 203 (1982) 15–23.

211 D.M. Templeton, B. Sarkar, Peptide and carbohydrate

complexes in human kidney, Biochem. J. 230 (1985) 35–42.

212 P.F. Predki, C. Harford, P. Brar, B. Sarkar, Further

characterization of the N-terminal copper(II)- and nickel(II)-

binding motif of proteins. Studies of metal binding to

chicken serum albumin and the native sequence peptide,

Biochem. J. 287 (1992) 211–215.

213 L.W. Donaldson, N.R. Skrynnikov, W.Y. Choy, D.R.

Muhandiram, B. Sarkar, J.D. Forman-Kay, L.E. Kay,

Structural characterization of proteins with an attached

ATCUN motif by paramagnetic relaxation enhancement

NMR spectroscopy, J. Am. Chem. Soc. 123 (2001) 9843–

9847.

214 J. Crowe, H. Dobeli, R. Gentz, E. Hochuli, D. Stuber,

K. Henco, 6xHis-Ni-NTA chromatography as a superior

technique in recombinant protein expression/purification, in:

A.J. Harwood (Ed.), Methods in Molecular Biology, Humana

Press, Totowa, NJ, 1994, pp. 371–387.

215 J.W. Bauman, J. Liu, C.D. Klaassen, Production of

metallothionein and heat-shock proteins in response to

metals, Fundam. Appl. Toxicol. 21 (1993) 15–22.

216 M. Van Soestbergen, F.W. Sunderman Jr., 63Ni complexes

in rabbit serum and urine after injection of 63NiCl2, Clin.

Chem. 18 (1972) 1478–1484.

217 N. Asato, M. van Soestbergen, F.W. Sunderman Jr., Binding

of 63Ni(II) to ultrafiltrable constituents of rabbit serum in

vivo and in vitro, Clin. Chem. 21 (1975) 521–527.

218 W.M. Callan, F.W. Sunderman Jr., Species variations in

binding of 63Ni(II) by serum albumin, Res. Commun. Chem.

Pathol. Pharmacol. 5 (1973) 459–474.

219 J.P. Laussac, B. Sarkar, Characterization of the copper(II)-

and nickel(II)-transport site of human serum albumin.

Studies of copper(II) and nickel(II) binding to peptide 1–24

of human serum albumin by 13C and 1H NMR spectroscopy,

Biochemistry 23 (1984) 2832–2838.

220 W. Bal, J. Christodoulou, P.J. Sadler, A. Tucker, Multi-metal

binding site of serum albumin, J. Inorg. Biochem. 70 (1998)

33–39.

221 K. Nakamuro, Y. Sayato, Chemical forms of nickel in rat

plasma, kidney cytosol, and urine after administration of

63NiCl2, Eisei Kagaku 35 (1989) 19–29.

222 S. Nomoto, M.D. McNeely, F.W. Sunderman Jr., Isolation of

a nickel _2-macroglobulin from rabbit serum, Biochemistry

10 (1971) 1647–1651.

223 S. Nomoto, F.W. Sunderman Jr., Presence of nickel in

alpha-2 macroglobulin isolated from human serum by high

performance liquid chromatography, Ann. Clin. Lab. Sci. 18

(1988) 78–84.

224 M.I. Decsy, F.W. Sunderman Jr., Binding of 63Ni to rabbit

serum _2-macroglobulin in vivo and in vitro, Bioinorg.

Chem. 3 (1974) 87–94.

225 A.W. Abdulwajid, B. Sarkar, Nickel-sequestering renal

glycoprotein, Proc. Natl. Acad. Sci. U.S.A. 80 (1983) 4509–

4512.

226 M.C. Herlant-Peers, H.F. Hildebrand, J.P. Kerckaert, In

vitro and in vivo incorporation of 63Ni(II) into lung and

liver subcellular fractions of Balb/C mice, Carcinogenesis 4

(1983) 387–392.

227 A. Oskarsson, H. Tjalve, Binding of 63Ni by cellular

constituents in some tissues of mice after the administration

of 63NiCl2, and 63Ni(CO)4, Acta Pharmacol. Toxicol. 45

(1979) 306–314.

228 F.W. Sunderman Jr., E.R. Costa, C. Fraser, G. Hui, J.L.

Levine, T.P.H. Tse, 63Ni-constituents in renal cytosol of rats

after injection of 63NiCl2, Ann. Clin. Lab. Sci. 11 (1981)

488–496.

229 F.W. Sunderman Jr., B.L. Mangold, S.H.Y. Wong, S.K.

Shen, M.C. Reid, I. Jansson, High-performance sizeexclusion

chromatography of 63Ni-constituents in renal

cytosol and microsomes from 63NiCl2 treated rats, Res.

Commun. Chem. Pathol. Pharmacol. 39 (1983) 477–492.

230 D.M. Templeton, B. Sarkar, Nickel binding to the C-terminal

tryptic fragment of a peptide from human kidney, Biochem.

Biophys. Acta 884 (1986) 382–386.

231 C. Harford, B. Sarkar, Neuromedin C binds Cu(II) and Ni(II)

via the ACTUN motif: implications for the CNS and cancer

growth, Biochem. Biophys. Res. Commun. 209 (1995) 877–

882.

232 E. Nieboer, A.R. Stafford, S.L. Evans, J. Dolovich, in: F.W.

Sunderman Jr., (Ed.), Nickel in the Human Environment,

Oxford University Press, Oxford, 1984, pp. 321–331.

233 K. Kondo, T. Ozaki, Y. Nakamura, S. Sakiyama, DAN gene

product has an affinity for Ni2+, Biochem. Biophys. Res.

Commun. 216 (1995) 209–215.

234 T. Ozaki, Y. Nakamura, H. Enomoto, M. Hirose, S.

Sakiyama, Overexpression of DAN gene product in normal

rat fibroblasts causes a retardation of the entry into the S

phase, Cancer Res. 55 (1995) 895–900.

235 F.W. Sunderman Jr., A.H. Varghese, O.S. Kroftova, S.

Grbac-Ivankovic, J. Kotyza, A.K. Datta, M. Davis, W.

Bal, K.S. Kasprzak, Characterization of pNiXa, a serpin of

Xenopus laevis oocytes and embryos, and its histidine-rich,

Ni(II)-binding domain, Mol. Reprod. Dev. 44 (1996) 507–

524.

236 J. Kotyza, A.H. Varghese, G. Korza, F.W. Sunderman Jr.,

Interaction of serine proteinases with pNiXa, a serpin from

Xenopus oocytes and embryos, Biochim. Biophys. Acta.

1382 (1998) 266–276.

237 K. Antonijczuk, O.S. Kroftova, A.H. Varghese, A.

Antonijczuk, D.C. Henjum, G. Korza, J. Ozols, F.W.

Sunderman Jr., The 40 kDa 63Ni(2+)-binding protein

(pNiXc) on western blots of Xenopus laevis oocytes

and embryos is the monomer of fructose-1,6-bisphosphate

aldolase A, Biochim. Biophys. Acta. 1247 (1995) 81–89.

238 S. Grbac-Ivankovic, K. Antonijczuk, A.H. Varghese, M.C.

Plowman, A. Antonijczuk, G. Korza, J. Ozols, F.W.

Sunderman Jr., Lipovitellin 2 beta is the 31 kD Ni(2+)-

binding protein (pNiXb) in Xenopus oocytes and embryos,

Mol. Reprod. Dev. 38 (1994) 256–263.

239 D. Gorlich, S. Prehn, R.A. Laskey, E. Hartmann, Isolation

of a protein that is essential for the first step of nuclear

protein import, Cell 79 (1994) 767–778.

K.S. Kasprzak et al. / Mutation Research 533 (2003) 67–97 95

240 H.C. Pace, P.N. Garrison, A.K. Robinson, L.D. Barnes, A.

Draganescu, A. Rosler, G.M. Blackburn, Z. Siprashvili, C.M.

Croce, K. Huebner, C. Brenner, Genetic, biochemical, and

crystallographic characterization of Fhit-substrate complexes

as the active signaling form of Fhit, Proc. Natl. Acad. Sci.

U.S.A. 95 (1998) 5484–5489.

241 M.A. Zoroddu, T. Kowalik-Jankowska, H. Kozlowski,

K. Salnikow, M. Costa, Ni(II) and Cu(II) binding with

a 14-aminoacid sequence of Cap43 protein, TRSRSHTSEGTRSR,

J. Inorg. Biochem. 84 (2001) 47–54.

242 S. Oshiro, K. Nozawa, M. Hori, C. Zhang, Y. Hashimoto,

S. Kitajima, K. Kawamura, Modulation of iron regulatory

protein-1 by various metals, Biochem. Biophys. Res.

Commun. 290 (2002) 213–218.

243 K.S. Kasprzak, M.P. Waalkes, L.A. Poirier, Antagonism by

essential divalent metals and amino acids of nickel(II)–DNA

binding in vitro, Toxicol. Appl. Pharmacol. 82 (1986) 336–

343.

244 W. Bal, H. Kozlowski, K.S. Kasprzak, Molecular models in

nickel carcinogenesis, J. Inorg. Biochem. 79 (2000) 213–

218.

245 W. Bal, M. Jezowska-Bojczuk, K.S. Kasprzak, Binding of

Ni(II) and Cu(II) to the N-terminal sequence of human

protamine HP2, Chem. Res. Toxicol. 10 (1997) 906–914.

246 W. Bal, J. Lukszo, M. Jezowska-Bojczuk, K.S. Kasprzak,

Interactions of nickel(II) with histones. Stability and solution

structure of complexes with CH3CO-Cys-Ala-Ile-His-NH2,

a putative metal binding sequence of histone H3, Chem.

Res. Toxicol. 8 (1995) 683–692.

247 K. Luger, A.W. Mader, R.K. Richmond, D.F. Sargent, T.J.

Richmond, Crystal structure of the nucleosome core particle

at 2.8 Å resolution, Nature 389 (1997) 251–260.

248 W. Bal, J. Lukszo, K. Bialkowski, K.S. Kasprzak, Interactions

of nickel(II) with histones: interactions of Ni(II) with

CH3CO-Thr-Glu-Ser-His-His-Lys-NH2, a peptide modeling

the potential metal binding site in the “C-tail” region of

histone H2A, Chem. Res. Toxicol. 11 (1998) 1014–1023.

249 M.A. Zoroddu, L. Schinocca, T. Kowalik-Jankowska, H.

Kozlowski, K. Salnikow, M. Costa, Molecular mechanisms

in nickel carcinogenesis: modeling Ni(II) binding site in

histone H4, Environ. Health Perspect. 110 (Suppl. 5) (2002)

719–723.

250 W. Bal, V. Karantza, E.N. Moudrianakis, K.S. Kasprzak,

Interaction of nickel(II) with histones: in vitro binding of

Ni(II) to the core histone tetramer, Arch. Biochem. Biophys.

364 (1999) 161–166.

251 A. Krezel, W. Szczepanik, M. Sokolowska, M. Jezowska-

Bojczuk, W. Bal, Correlations between complexation modes

and redox activities of Ni(II)–GSH complexes, Chem. Res.

Toxicol. 16 (2003) 855–864.

252 W. Bal, R. Liang, J. Lukszo, S.H. Lee, M. Dizdaroglu, K.S.

Kasprzak, Nickel(II) specifically cleaves the C-terminal tail

of the major variant of histone H2A and forms oxidative

damage-mediating complex with the cleaved-off octapeptide,

Chem. Res. Toxicol. 13 (2000) 616–624.

253 J. Ausio, D.W. Abbott, The many tales of a tail: carboxyterminal

tail heterogeneity specializes histone H2A variants

for defined chromatin function, Biochemistry 41 (2002)

5945–5949.

254 K.S. Kasprzak, Possible role of oxidative damage in metalinduced

carcinogenesis, Cancer Invest. 13 (1995) 411–430.

255 K.S. Kasprzak, Oxidative DNA and protein damage in

metal-induced toxicity and carcinogenesis, Free Radic. Biol.

Med. 32 (2002) 958–967.

256 X. Huang, C.B. Klein, M. Costa, Crystalline Ni3S2

specifically enhances the formation of oxidants in the

nuclei of CHO cells as detected by dichlorofluorescein,

Carcinogenesis 15 (1994) 545–548.

257 K. Salnikow, M. Gao, V. Voitkun, X. Huang, M. Costa,

Altered oxidative stress responses in nickel resistant

mammalian cells, Cancer Res. 54 (1994) 6407–6412.

258 M.C. Herrero, C. Alvarez, J. Cartana, C. Blade, L. Arola,

Nickel effects on hepatic amino acids, Res. Commun. Chem.

Pathol. Pharmacol. 79 (1993) 243–248.

259 W. Li, Y. Zhao, I.N. Chou, Alterations in cytoskeletal protein

sulfhydryls and cellular glutathione in cultured cells exposed

to cadmium and nickel ions, Toxicology 77 (1993) 65–79.

260 D.W. Margerum, S.L. Anliker, Nickel(III) chemistry and

properties of the peptide complexes of Ni(II) and Ni(III), in:

J.R. Lancaster (Ed.), The Bioinorganic Chemistry of Nickel,

VCH, New York, 1988, pp. 29–51.

261 K.S. Kasprzak, Oxidative DNA damage in metal-induced

carcinogenesis, in: L.W. Chang, L. Magos, T. Suzuki, (Eds.),

Toxicology of Metals, Lewis Publishers, Boca Raton, 1996,

pp. 299–320.

262 J.R. Landolph, Role of free radicals in metal-induced

carcinogenesis, in: H. Sigel, A. Sigel (Eds.), Metal Ions

in Biological Systems, vol. 36, Marcel Dekker, New York,

1999, pp. 445–483.

263 K.S. Kasprzak, G.S. Buzard, The role of metals in oxidative

damage and redox cell signaling derangement, in: J.

Koropatnick, R. Zalups (Eds.), Molecular Biology and

Toxicology of Metals, Taylor and Francis, London, 2000,

pp. 477–527.

264 D. Costa, J. Guignard, H. Pezerat, Production of free radicals

arising from the surface activity of minerals and oxygen. Part

II. Arsenides, sulfides, and sulfoarsenides of iron, nickel,

and copper, Toxicol. Ind. Health 5 (1989) 1079–1097.

265 J.E. Lee, R.B. Ciccarelli, K.W. Wetterhahn Jenette,

Solubilization of the carcinogen nickel subsulfide and

its interaction with deoxyribonucleic acid and protein,

Biochemistry 21 (1982) 771–778.

266 L.K. Tkeshelashvili, T.M. Reid, T.J. McBride, L.A. Loeb,

Nickel induces a signature mutation for oxygen free radical

damage, Cancer Res. 53 (1993) 4172–4174.

267 W. Bal, J. Lukszo, K.S. Kasprzak, Mediation of oxidative

DNA damage by nickel(II) and copper(II) complexes with

the N-terminal sequence of human protamine HP2, Chem.

Res. Toxicol. 10 (1997) 915–921.

268 W. Bal, J. Wojcik, M. Maciejczyk, P. Grochowski, K.S.

Kasprzak, Induction of a secondary structure in the

N-terminal pentadecapeptide of human protamine HP2

through Ni(II) coordination. An NMR study, Chem. Res.

Toxicol. 13 (2000) 823–830.

96 K.S. Kasprzak et al. / Mutation Research 533 (2003) 67–97

269 E.R. Stadtman, Oxidation of free amino acids and amino

acid residues in proteins by radiolysis and by metal-catalyzed

reactions, Annu. Rev. Biochem. 62 (1993) 797–821.

270 J.R. Requena, C.-C. Chao, L.R. Levine, E.R. Stadtman,

Glutamic and aminoadipic semialdehydes are the main

carbonyl products of metal-catalyzed oxidation of proteins,

Proc. Natl. Acad. Sci. U.S.A. 98 (2001) 69–74.

271 E.R. Stadtman, B.S. Berlett, Fenton chemistry: amino acid

oxidation, J. Biol. Chem. 266 (1991) 17201–17211.

272 M.A. Zoroddu, T. Kowalik-Jankowska, H. Kozlowski, H.

Molinari, K. Salnikow, L. Broday, M. Costa, Interaction of

Ni(II) and Cu(II) with a metal binding sequence of histone

H4: AKRHRK, a model of the H4 tail, Biochim. Biophys.

Acta 1475 (2000) 163–168.

273 J.M. Berg, Potential metal-binding domains in nucleic acid

binding proteins, Science 232 (1986) 485–487.

274 S.E. Bryan, Heavy metals in the cell’s nucleus, in: G.L.

Eichhorn, L.G. Marzili (Eds.), Metal Ions in Genetic

Information Transfer, Elsevier, New York, 1981, pp. 87–101.

275 A. Leonard, Chromosome damage in individuals exposed

to heavy metals, in: H. Sigel (Ed.), Metal Ions in

Biological Systems, vol. 20, Marcel Dekker, New York,

1986, pp. 229–258.

276 K.S. Kasprzak, L.A. Poirier, Effects of calcium(II) and

magnesium(II) on nickel(II) uptake and stimulation of

thymidine incorporation into DNA in the lungs of strain A

mice, Carcinogenesis 6 (1985) 1819–1821.

277 A.V. Peskin, L. Shlyahova, Cell nuclei generate DNAnicking

superoxide radicals, FEBS Lett. 194 (1986) 317–

321.

278 M. Dizdaroglu, Chemical determination of oxidative base

damage in DNA by gas chromatography–mass spectrometry,

Methods Enzymol. 234 (1994) 3–16.

279 Z. Nackerdien, K.S. Kasprzak, G. Rao, B. Halliwell, M.

Dizdaroglu, Nickel(II)- and cobalt(II)-dependent damage by

hydrogen peroxide to the DNA bases in isolated human

chromatin, Cancer Res. 51 (1991) 5837–5842.

280 X. Huang, J. Kitahara, A. Zhitkovich, K. Dowjat, M.

Costa, Heterochromatic proteins specifically enhance nickelinduced

8-oxo-dG formation, Carcinogenesis 16 (1995)

1753–1759.

281 K.S. Kasprzak, K. Bialkowski, Inhibition of antimutagenic

enzymes, 8-oxo-dGTPases, by carcinogenic metals. Recent

developments, J. Inorg. Biochem. 79 (2000) 231–236.

282 K.S. Kasprzak, B.A. Diwan, J.M. Rice, M. Misra, C.W.

Riggs, R. Olinski, M. Dizdaroglu, Nickel(II)-mediated

oxidative DNA base damage in renal and hepatic chromatin

of pregnant rats and their fetuses. Possible relevance to

carcinogenesis, Chem. Res. Toxicol. 5 (1992) 809–815.

283 M. Misra, R. Olinski, M. Dizdaroglu, K.S. Kasprzak,

Enhancement by L-histidine of nickel(II)-induced DNA–

protein cross-linking and oxidative DNA base damage in

the rat kidney, Chem. Res. Toxicol. 6 (1993) 33–37.

284 K.S. Kasprzak, P. Jaruga, T.H. Zastawny, S.L. North,

C.W. Riggs, R. Olinski, M. Dizdaroglu, Oxidative DNA

base damage and its repair in kidneys and livers of

nickel(II)-treated male F344 rats, Carcinogenesis 18 (1997)

271–277.

285 S. Kawanishi, S. Inoue, S. Oikawa, N. Yamashita, S.

Toyokuni, M. Kawanishi, K. Nishino, Oxidative DNA

damage in cultured cells and rat lungs by carcinogenic nickel

compounds, Free Radic. Biol. Med. 31 (2001) 108–116.

286 K.S. Kasprzak, M. Misra, R.E. Rodriguez, S.L. North,

Nickel-induced oxidation of renal DNA guanine residues in

vivo and in vitro, Toxicologist 11 (1991) 233.

287 C.B. Klein, K. Frenkel, M. Costa, The role of oxidative

processes in metal carcinogenesis, Chem. Res. Toxicol. 4

(1991) 592–604.

288 A.M. Standeven, K.E. Wetterhahn, Is there a role for

reactive oxygen species in the mechanism of chromium(VI)

carcinogenesis? Chem. Res. Toxicol. 4 (1991) 616–625.

289 K.S. Kasprzak, R.M. Bare, In vitro polymerization of

histones by carcinogenic nickel compounds, Carcinogenesis

10 (1989) 621–624.

290 U. Saplakoglu, M. Iscan, M. Iscan, DNA single-strand

breakage in rat lung, liver and kidney after single and

combined treatments of nickel and cadmium, Mutat. Res.

394 (1997) 133–140.

291 Y. Cai, Z. Zhuang, DNA damage in human peripheral

blood lymphocyte caused by nickel and cadmium (Chin.),

Zhonghua Yu Fang Yi Xue Za Zhi 33 (1999) 75–77.

292 R. Liang, S. Senturker, X. Shi, W. Bal, M. Dizdaroglu, K.S.

Kasprzak, Effect of Ni(II) and Cu(II) on DNA interaction

with the N-terminal sequence of human protamine P2:

enhancement of binding and mediation of oxidative DNA

strand scission and base damage, Carcinogenesis 20 (1999)

893–898.

293 S. Kawanishi, S. Inoue, K. Yamamoto, Site-specific DNA

damage by nickel(II) ion in the presence of hydrogen

peroxide, Carcinogenesis 12 (1989) 2231–2235.

294 R.M. Schaaper, R.M. Koplitz, L.K. Tkeshelashvili, L.A.

Loeb, Metal-induced lethality and mutagenesis: possible role

of apurinic intermediates, Mutat. Res. 177 (1987) 179–188.

295 K.S. Kasprzak, L. Hernandez, Enhancement of hydroxylation

and deglycosylation of 2_-deoxyguanosine by carcinogenic

nickel compounds, Cancer Res. 49 (1989) 5964–5968.

296 A.P. Grollman, M. Moriya, Mutagenesis by 8-oxoguanine:

an enemy within, Trends Genet. 9 (1993) 246–249.

297 A. Hartwig, Current aspects in metal genotoxicity, BioMetals

8 (1995) 3–11.

298 S.A. Weitzman, Influence of oxygen radical injury on DNA

methylation, Mutat. Res. 386 (1997) 141–152.

299 M.K. Morrison, J.M. Kotler, B.D. Martin, K.D. Sugden,

Oxidized guanine lesions as modulators of gene transcription,

Biochemistry 42 (2003) 9761–9770.

300 G.S. Buzard, K.S. Kasprzak, Possible roles of nitric oxide

and redox cell signaling in metal-induced toxicity and

carcinogenesis: a review, J. Environ. Pathol. Toxicol. Oncol.

19 (2000) 179–199.

301 S. Bergelson, R. Pinkus, V. Daniel, Intracellular glutathione

levels regulate fos/jun induction and activation of glutathione

S-transferase gene expression, Cancer Res. 54 (1994) 36–40.

302 M. Meyer, R. Schreck, P.A. Baeuerle, H2O2 and antioxidants

have opposite effects on activation of NFkB and AP-1 in

intact cells: AP-1 as secondary antioxidant-responsive factor,

EMBO J. 12 (1993) 2005–2015.

K.S. Kasprzak et al. / Mutation Research 533 (2003) 67–97 97

303 M. Costa, J.E. Sutherland, W. Peng, K. Salnikow, L. Broday,

T. Kluz, Molecular biology of nickel carcinogenesis, Mol.

Cell. Biochem. 222 (2001) 205–211.

304 P. Burtayre, J. Liquier, J. Taboury, L. Pizzorni, J.F. Labarre,

E. Taillandier, Z-form induction in DNA by carcinogenic

nickel compounds. An optical spectroscopy study, in: F.W.

Sunderman Jr., (Ed.), Nickel in the Human Environment,

vol. 53, IARC Scientific Publications, Lyon, 1984, pp. 227–

234.

305 F.E. Rossetto, E. Nieboer, The interaction of metal ions

with synthetic DNA: induction of conformational and

structural transitions, J. Inorg. Biochem. 54 (1994) 167–

186.

306 H. Sigel, Metal ions and hydrogen peroxide. XXIX. On

the kinetics and mechanism of the catalyse-like activity of

nickel(II) and nickel(II) amine complexes, J. Coord. Chem.

3 (1974) 235–247.

307 D.R. Lloyd, P.L. Carmichael, D.H. Phillips, Comparison

of the formation of 8-hydroxy-2_-deoxyguanosine and

single- and double-strand breaks in DNA mediated by

fenton reactions, Chem. Res. Toxicol. 11 (1998) 420–

427.

308 F.W. Sunderman Jr., C.E. Selin, The metabolism of nickel-

63 carbonyl, Toxicol. Appl. Pharmacol. 1 (1968) 297–318.

309 K.S. Kasprzak, F.W. Sunderman Jr., The metabolism of

nickel carbonyl-14C, Toxicol. Appl. Pharmacol. 15 (1969)

295–303.

310 S.E. Rokita, C.J. Burrows, Nickel- and cobalt-dependent

oxidation and crosslinking of proteins, Met. Ions Biol. Syst.

38 (2001) 289–311.

311 C.J. Burrows, J.G. Muller, Oxidative nucleobase modifi-

cations leading to strand scission, Chem. Rev. 98 (1998)

1109–1152.

312 H. Dally, A. Hartwig, Induction and repair inhibition of

oxidative DNA damage by nickel(II) and cadmium(II) in

mammalian cells, Carcinogenesis 18 (1997) 1021–1026.

313 G.L. Semenza, Regulation of mammalian O2 homeostasis

by hypoxia-inducible factor 1, Annu. Rev. Cell. Dev. Biol.

15 (1999) 551–578.

314 E. Horak, E.R. Zygowicz, R. Tarabishy, J.M. Mitchell,

F.W. Sunderman Jr., Effects of nickel chloride and nickel

carbonyl upon glucose metabolism in rats, Ann. Clin. Lab.

Sci. 8 (1978) 476–482.

315 K.K. Graven, R.J. McDonald, H.W. Farber, Hypoxia

regulation of endothelial glyceraldehyde-3-phosphate dehydrogenase,

Am. J. Physiol. 43 (1998) 347–355.

316 O. Warburg, On respiratory impairment in cancer cells,

Science 123 (1956) 309–314.

317 J. Chesney, R. Mitchell, F. Benigni, M. Bacher, L. Spiegel,

Y. Al-Abed, J.H. Han, C. Metz, R. Bucala, An inducible

gene product for 6-phosphofructo-2-kinase with an AU-rich

instability element: role in tumor cell glycolysis and the

Warburg effect, Proc. Natl. Acad. Sci. U.S.A. 96 (1999)

3047–3052.