Impairment of hepatic microsomal drug metabolism in the rat during daily disulfiram administration

Abstract

Male rats were given 0.1 or 0.4 g/kg of disulfiram (DS) daily by gavage for up to 12 days, in order to study the effects of chronic DS administration on hepatic microsoma] drug metabolism. Administration of 0.4 g/kg of DS resulted in significant impairment of aniline (ANL) hydroxylase after 1 day. but 2 days of DS treatment were required for significant inhibition of ethylmorphine (EtM) metabolism and depression of cytochrome P-450 levels. At this time, maximum impairment of ANL and EtM metabolism and maximum reduction of cytochrome P-450 levels were seen. Continued administration of DS for 10 additional days produced no further change in these parameters. ANL hydroxylase was also significantly reduced in treated animals throughout a 12-day period during which 0.1 g/kg of DS was given. EtM N-demethylase activity and cytochrome P-450 levels were also reduced in animals so treated, but not until DS had been given for at least 5 days. However, by the end of the 12-day experimental period. EtM metabolism and cytochrome P-450 levels had returned almost to control levels and only ANL hydroxylase was significantly different from control activity. Daily DS administration (0.4 g/kg produced small but significant increases in microsomal cytochrome b 5 levels and in NADPH-cytochrome c reductase activity, whereas NADPH oxidase and NADPH-cytochrome P-450 reductase activities were significantly lower in treated rats. In addition to these effects in vivo, DS competitively inhibited EtM N-demethylase in vitro and bound to cytochrome P-450, producing a type I difference spectrum, thus providing additional mechanisms to account for impairment in vivo of drug metabolism by DS.