Inhibitory effects of carbon tetrachloride on dimethylnitrosamine metabolism and DNA alkylation.

Abstract

The effect of CCl4 pretreatment (dose range from 0.5 to 2.0 ml/kg body weight) on the pathways of dimethylnitrosamine (DMN) metabolism was investigated. The oxidative-N-demethylation by the enzymes, DMN-demethylase I and II operating at low (4 mM) and high (200 mM) substrate concentration, respectively, was greatly reduced in a dose-dependent manner. In addition, the generation of an electrophilic intermediate capable of methylating DNA, specifically at the N-7 and O-6 positions of guanine, was completely inhibited by CCl4 (0.5 ml/kg body weight) pretreatment. When indole feeding (1% in the diet for 8 days prior to CCl4 administration) was employed as a means to enhance DMN-demethylase activities, it was found that the reduction of DMN-demethylase activities was more pronounced in these rats than in the controls. In agreement with earlier findings, 7-methylguanine and O6-methylguanine were not detectable in the CCl4 pretreated group. These results suggest that CCl4 exerts a strong inhibitory action on hepatic DMN metabolism, in particular on the pathway leading to alkylation of DNA guanine. This phenomenon may explain the protective role of CCl4 against DMN-induced hepatotoxicity and perhaps, carcinogenicity, believed to be closely associated with the abnormal modifications of DNA.