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Chloroform, carbon tetrachloride and glutathione depletion induce secondary genotoxicity in liver cells via oxidative stress.

Abstract：

:Chemical carcinogens are generally classified as genotoxic or non-genotoxic. However, weak genotoxicity at high concentrations is sometimes observed and interpretation is often problematic. In addition, certain rodent carcinogens exert their effects at doses associated with cytotoxicity and compensatory hyperplasia may be a contributing factor to tumourogenesis. We hypothesise that certain substances, at high concentrations, can induce an oxidative stress via the depletion of glutathione (GSH) and other antioxidant defences and that this may lead to indirect genotoxicity, that could contribute to carcinogenicity. In support of this, human HepG2 cells treated with buthionine sulphoximine (BSO) to deplete GSH, exhibited DNA strand breaks alongside elevated 8-oxodeoxyguanosine (8-oxodG) and malondialdehyde deoxyguanosine (M(1)dG) adducts under conditions associated with lipid peroxidation. Chloroform and carbon tetrachloride are rodent carcinogens with characteristics as described above. In female rat hepatocytes, chloroform treatment resulted in a small dose-dependent increase in M(1)dG adducts (4 mM and above), DNA strand breakage (8 mM and above) and lipid peroxidation, in the absence of any associated increase in DNA oxidation. GSH depletion only occurred in association with cytotoxicity (20 mM; lactate dehydrogenase release). Alongside lipid peroxidation, carbon tetrachloride (1 and 4 mM) produced a small elevation in M(1)dG adducts and DNA strand breaks and increases in 8-oxodG were observed at the threshold of, and concomitant with, cytotoxicity (4 mM). These effects may contribute to high dose genotoxicity and carcinogenicity. Non-linearity in the dose response is expected on the basis of depletion of antioxidants, and therefore, a pragmatic threshold for biologically relevant responses should exist.

journal_name

Toxicology

journal_title

Toxicology

authors

Beddowes EJ,Faux SP,Chipman JK

doi

10.1016/s0300-483x(03)00058-1

keywords:

subject

Has Abstract

pub_date

2003-05-03 00:00:00

pages

101-15

issue

2-3

eissn

0300-483X

issn

1879-3185

pii

S0300483X03000581

journal_volume

187

pub_type

杂志文章

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Chloroform, carbon tetrachloride and glutathione depletion induce secondary genotoxicity in liver cells via oxidative stress.