Effect of chlorpromazine hydrochloride on carcinogen-metabolizing enzymes: liver microsomal dimethylnitrosamine demethylase, 4-dimethylaminoazobenzene reductase, and aryl hydrocarbon hydroxylase.

Investigation of the effect of chlorpromazine hydrochloride (CPZ) on some enzymes involved in the metabolism of the carcinogens 4-dimethylaminoazobenzene (DAB), benzo[a]pyrene, and dimethylnitrosamine (DMN) revealed that CPZ inhibited hepatic microsomal DAB reductase, aryl hydrocarbon hydroxylase, and DMN demethylase II but markedly activated DMN demethylase I. Inhibition of these enzymes in vitro was proportional to the concentrations of CPZ. The effect of CPZ on DMN demethylase also depended on the concentrations of DMN and CPZ in the incubation mixture. Mechanisms to account for the inhibition of DAB reductase were suggested. Aryl hydrocarbon hydroxylase and DMN demethylase II activities of the 100,000 x g hepatic microsomal fraction were activated by 33 and 61%, respectively, over the control values after a single injection of CPZ into F344 rats, but no effect on DAB reductase and DMN demethylase I activities was observed. Microsomal concentrations of protein and cytochrome P450 were not appreciably altered by CPZ treatment, whereas the level of microsomal NADPH cytochrome c reductase was slightly increased over control values. A similar effect on the drug-metabolizing enzymes was found during pretreatment of rats with CPZ for 5 days, except that the NADPH cytochrome c reductase was increased by 33% over the control values.