EPR Evidence for Chromium(V) Binding to Phosphate and Pyrophosphate:  Implications for Chromium(V)−DNA Interactions

Sugden, Kent D.; Wetterhahn, Karen E.

doi:10.1021/ic960199+

Cited by 36 publications

(24 citation statements)

References 14 publications

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“…Instead, Cr(III) participates in coordinate covalent interactions with various cellular macromolecules (reviewed in [33;35]). In addition, Cr(III), a trivalent cation, displays an affinity for the phosphodiester backbone which is believed to be a primary mode of initial attachment to DNA by Cr [33;35;54;61]. A number of lesions generated by Cr can inhibit replication fork progression [32;33;62;63] and our work is consistent with Polζ-dependent TLS playing an important, albeit mutagenic, role in bypassing Cr-induced replication arresting lesions.…”

Section: Discussionmentioning

confidence: 99%

DNA polymerase ζ is essential for hexavalent chromium-induced mutagenesis

O’Brien

Witcher

Brooks

et al. 2009

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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Translesion synthesis (TLS) is a unique DNA damage tolerance mechanism involved in the replicative bypass of genetic lesions in favor of uninterrupted DNA replication. TLS is critical for the generation of mutations by many different chemical and physical agents, however, there is no information available regarding the role of TLS in carcinogenic metal-induced mutagenesis. Hexavalent chromium (Cr(VI))-containing compounds are highly complex genotoxins possessing both mutagenic and clastogenic activities. The focus of this work was to determine the impact that TLS has on Cr(VI)-induced mutagenesis in S. cerevisiae. Wild-type yeast and strains deficient in TLS polymerases (i.e. Polζ (rev3), Polη (rad30)) were exposed to Cr(VI) and monitored for cell survival and forward mutagenesis at the CAN1 locus. In general, TLS deficiency had little impact on Cr(VI)-induced clonogenic lethality or cell growth. rad30 yeast exhibited higher levels of basal and induced mutagenesis compared to Wt and rev3 yeast. In contrast, rev3 yeast displayed attenuated Cr(VI)-induced mutagenesis. Moreover, deletion of REV3 in rad30 yeast (rad30 rev3) resulted in a significant decrease in basal and Cr(VI) mutagenesis relative to Wt and rad30 single mutants indicating that mutagenesis primarily depended upon Polζ. Interestingly, rev3 yeast were similar to Wt yeast in susceptibility to Cr(VI)-induced frameshift mutations. Mutational analysis of the CAN1 gene revealed that Cr(VI)-induced base substitution mutations accounted for 83.9% and 100.0% of the total mutations in Wt and rev3 yeast, respectively. Insertions and deletions comprised 16.1% of the total mutations in Cr(VI) treated Wt yeast but were not observed rev3 yeast. This work provides novel information regarding the molecular mechanisms of Cr(VI)-induced mutagenesis and is the first report demonstrating a role for TLS in the fixation of mutations induced by a carcinogenic metal.

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Section: Discussionmentioning

confidence: 99%

DNA polymerase ζ is essential for hexavalent chromium-induced mutagenesis

O’Brien

Witcher

Brooks

et al. 2009

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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“…Os mesmos investigadores observaram que, em comparação com o Cr(pic) 3 , o potencial do complexo 9 e do LMWCr para clivar a molécula do ADN é muito menor nas condições fisiológicas 78 . Embora LMWCr seja biologicamente ativo e tenha um LD 50 alto, é susceptível à hidrólise em condições ácidas e, conseqüentemente, não pode ser ingerido oralmente sem degradação 79 . Assim sendo, supõe-se que o complexo 9 venha a ser um suplemento nutricional mais seguro para substituir o Cr(pic) 3 .…”

Section: A Relevância Biológica Do Crômio Trivalenteunclassified

O impacto do crômio nos sistemas biológicos

Ferreira¹

2002

Quím. Nova

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Recebido em 17/11/00; aceito em 19/12/01 THE IMPACT OF CHROMIUM ON BIOLOGICAL SYSTEMS. The impact of biological chromium's activity may be beneficial or not. This review presents the most relevant chemical aspects of these "two faces" of chromium by covering first, the efforts toward a clearer understanding of the carcinogenic properties of chromium compounds. The biomimetic chemistry of Cr(V) complexes illustrates the interactions of the intermediates formed by Cr(VI) reduction with DNA or oligonucleotides. The importance of trivalent chromium as an essential element is also emphasized by summarizing the recent results of the investigations on trinuclear chromium complexes as models of the cofactor responsible for the insulin activity, as well as good candidates for new nutritional supplements.Keywords: chromium; model compounds; DNA; insulin. INTRODUÇÃOCrômio trivalente é reconhecido atualmente como um elemento essencial no metabolismo de carbohidratos e lipídeos, sendo que sua função está relacionada com o mecanismo de ação da insulina [1][2][3][4] . A quantidade recomendada de crômio a ser consumida diariamente é de 50-200 mg e a falta desse elemento na alimentação pode causar sérias complicações na saúde, como diabete e problemas cardiovasculares 5 . Ao contrário do íon trivalente, no estado de oxidação VI, o crômio é classificado como composto mutagênico e carcinogênico em animais 6 . O dicromato e o óxido ou o ácido crômico estão entre os compostos de crômio economicamente mais importantes. Eles são utilizados na produção de tintas, como compostos de proteção de manufaturados de madeira ou couro 7 . No entanto, a questão da contaminação por Cr(VI) não é um problema que se restringe aos limites industriais ou aos que trabalham diretamente com os compostos, mas é também um problema ambiental (ver Figura 1), como reportado recentemente no caso das águas residuais contaminadas com crômio procedentes de curtumes em Minas Gerais 8 . Esta revisão tem como objetivo apresentar os aspectos químicos mais relevantes que conduzem às atividades distintas do crômio nos sistemas biológicos. A primeira parte focalizará as interações de compostos de crômio carcinogênicos com biomoléculas, e a química biomimética dos complexos de Cr(IV)/Cr(V). A relevância do crômio trivalente como um elemento traço essencial será apresentada no úl-timo tópico deste trabalho. Os leitores interessados em maiores detalhes sobre a bioquímica de tais sistemas poderão consultar os trabalhos que tratam dos aspectos benéficos [1][2][3][4][5] e tóxicos do crômio 4,6,[9][10][11] . A QUÍMICA AQUOSA DO CRÔMIONos sistemas fisiológicos o crômio pode ser encontrado nos estados de oxidação III-VI. Os compostos contendo Cr(VI), Cr(V) ou Cr(IV) são agentes oxidantes relativamente fortes em pH fisiológico e a estabilidade dos mesmos depende do pH e da concentração dos agentes redutores. A influência da natureza dos ligantes e do pH sobre a estabilidade, o potencial de óxido-redução dos complexos e as características principais de cada estado de oxidação estã...

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“…The pattern of DNA damage by Cr(V) and Cr(IV) includes strand breakage, 6 formation of Cr(III) ± DNA complexes, 7 and oxidation of nucleotides via phosphate-binding intermediates. 8 Recently, research on chromium toxicity has been heading towards studies of chromium compounds in intermediate oxidation states, mostly Cr(V).…”

Section: ¡mentioning

confidence: 99%

Comparative histological studies on liver of mice exposed to Cr(VI) and Cr(V) compounds

et al. 2002

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Chromium toxicity is strongly dependent on its oxidation state. Cr(VI) is carcinogenic and mutagenic, although its in vivo and in vitro toxic effects are related to its intracellular fate. Inside the cells, Cr(VI) is rapidly reduced to stable Cr(III). As Cr(V) and Cr(IV) species have been reported to be formed in the Cr(VI) reduction pathways, Cr(VI)induced damage is thought, at least in part, to arise from these hypervalent species. The study of Cr(VI) reduction mechanisms and the characterization of the effects of each reactive intermediate constitute important steps towards a better understanding of chromium toxicity. The purpose of this work is to enlarge the scope of Cr(VI)induced alterations in mouse to other chromium species. Our studies have led to the in situ preparation of a new Cr(V) complex, [CrV–BT]2–, a stable compound at neutral pH, which mimics Cr(VI) reduction intermediates. The effect of Cr(V) on the histology of mice liver is assessed and compared with similar Cr(VI) assays. Liver toxicity was examined after single administrations of Cr(VI) or [CrV–BT]2– to mice. Both compounds produced reversible hepatic damage in a time-dependent manner. However, Cr(V) toxic effects have proved to be more rapid than with Cr(VI), permitting the role of Cr(VI) intermediates formed during intracellular chromium reduction to be highlighted.

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EPR Evidence for Chromium(V) Binding to Phosphate and Pyrophosphate: Implications for Chromium(V)−DNA Interactions

Cited by 36 publications

References 14 publications

DNA polymerase ζ is essential for hexavalent chromium-induced mutagenesis

DNA polymerase ζ is essential for hexavalent chromium-induced mutagenesis

O impacto do crômio nos sistemas biológicos

Comparative histological studies on liver of mice exposed to Cr(VI) and Cr(V) compounds

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