In vitro effects of N-acetylcysteine on the mutagenicity of direct-acting compounds and procarcinogens.
N-Acetylcysteine (NAC), reduced (GSH) and oxidized (GSSG) glutathione were negative in the Ames test with 7 Salmonella strains, while L-cysteine was activated by rat liver S-9 fractions to metabolites mutagenic to strains TA102, TA97 and TA100. The mutagenic response in S. typhimurium strains (TA1535, TA98, TA100, TA102) and the levels of enzyme activities, responsible for NADP+ or GSSG reduction and for the utilization of NADPH or GSH in rat liver S-9 fractions, were investigated following in vitro preincubation of NAC with four direct-acting mutagens and six procarcinogens. Treatment with this nucleophilic and reducing compound resulted in a dose-related decrease of the direct mutagenicity of epichlorohydrin, hydrogen peroxide and, sharply, of 4-nitroquinolino-N-oxide and sodium dichromate. The mutagenicity of these compounds, both in the absence and in the presence of NAC, was decreased by rat liver S-9 fractions and to some extent by lung S-9 fractions. A diphasic effect was observed in the case of procarcinogens (cyclophosphamide, 2-aminofluorene, cigarette smoke condensate, Trp-P-2, aflatoxin B1 and benzo[a]pyrene), i.e., an enhancement of S-9 requiring mutagenicity at intermediate NAC doses, which could be ascribed to metabolic factors acting in vitro, and a loss of mutagenicity at high NAC doses, which could be ascribed to trapping of electrophilic metabolites. Out of the five S-9 enzyme activities under study, i.e., glucose-6-phosphate dehydrogenase, 6-phosphogluconate dehydrogenase, malic enzyme, GSH peroxidase and GSSG reductase, only the last one showed significant changes following mutagen and/or NAC treatment.
D000111:Acetylcysteine / Q000633:toxicity*; D000818:Animals; D001711:Biotransformation; D002273:Carcinogens / Q000633:toxicity*; D003545:Cysteine / Q000633:toxicity; D004347:Drug Interactions; D005978:Glutathione / Q000031:analogs & derivatives / Q000633:toxicity*; D019803:Glutathione Disulfide; D008862:Microsomes, Liver / Q000378:metabolism; D009152:Mutagenicity Tests; D009153:Mutagens; D009154:Mutation; D051381:Rats; D011919:Rats, Inbred Strains; D012486:Salmonella typhimurium / Q000187:drug effects
D002273:Carcinogens; D009153:Mutagens; D005978:Glutathione; D003545:Cysteine; D019803:Glutathione Disulfide; D000111:Acetylcysteine