Chloroform, carbon tetrachloride and glutathione depletion induce secondary genotoxicity in liver cells via oxidative stress.
Toxicology
; 187(2-3): 101-15, 2003 May 03.
Article
en En
| MEDLINE
| ID: mdl-12699900
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.
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Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Tetracloruro de Carbono
/
Cloroformo
/
Estrés Oxidativo
/
Hepatocitos
/
Glutatión
/
Mutágenos
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Female
/
Humans
Idioma:
En
Revista:
Toxicology
Año:
2003
Tipo del documento:
Article
País de afiliación:
Reino Unido