Document Type

Article

Publication Title

Environmental Health Perspectives

Publication Date

10-2002

Volume

110

Disciplines

Biochemistry | Chemistry | Life Sciences | Physical Sciences and Mathematics

Abstract

The hexavalent oxidation state of chromium [Cr(VI)] is a well-established human carcinogen, although the mechanism of cancer induction is currently unknown. Intracellular reduction of Cr(VI) forms Cr(V), which is thought to play a fundamental role in the mechanism of DNA damage by this carcinogen. Two separate pathways of DNA damage, an oxidative pathway and a metal-binding pathway, have been proposed to account for the lesions observed in cell systems. We have used a model Cr(V) complex, N,N´-ethylenebis(salicylidene-animato)oxochromium(V) [Cr(V)-Salen], to investigate the oxidative pathway of DNA damage and to elucidate the lesions generated from this oxidation process. Reaction of Cr(V)-Salen with synthetic oligonucleotides produced guanine-specific lesions that were not 8-oxo-2´-deoxyguanosine, based on the inability of iridium(IV) to further oxidize these sites. Oxidation products were identified using a 7,8-dihydro-8-oxo-2´-deoxyguanosine (8-oxo-G) containing oligonucleotide to increase the yields of product for identification by electrospray ionization mass spectrometry. The guanine-based lesions observed by mass spectrometry corresponded to the lesions guanidinohydantoin and spiroiminodihydantoin. The effects of these Cr(V)-Salen–induced lesions on DNA replication fidelity was assayed using a polymerase-based misincorporation assay. These lesions produced G→T transversion mutations and polymerase stops at levels greater than those observed for 8-oxo-G. These data suggest a model by which chromate can cause DNA damage leading to mutations and cancer. Key words: chromate, chromium(V), 7,8-dihydro-8-oxo-2´-deoxyguanine, guanidinohydantoin, oxidative damage, spiroiminodihydantoin. Environ Health Perspect 110(suppl 5):725–728 (2002). http://ehpnet1.niehs.nih.gov/docs/2002/suppl-5/725-728sudgen/abstract.html

Comments

Reproduced with permission from Environmental Health Perspectives.

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