Differences in the kinetics of benzpyrene hydroxylation by hepatic drug-metabolizing enzymes from phenobarbital and 3-methylcholanthrene-treated rats

Abstract

o-Benzyl-p-chlorophenol (BCP) is widely used as a broad spectrum disinfectant. Treatment of male Fischer 344 rats with BCP resulted in an increase in cytochrome P-450 content and an accompanying decrease in aryl hydrocarbon hydroxylase (AHH) activity in both liver and kidney microsomes. Several other drug-metabolizing enzymes were not affected by BCP treatment. However, in kidney, BCP induced NADPH-cytochrome c reductase and uridine diphosphate glucuronyl transferase activities and caused a small increase in total cytochrome P-450 content and glutathione concentration. The cytochrome P-450 isozymes induced by BCP were fractionated by high pressure liquid chromatography (HPLC). The HPLC profile following BCP treatment most closely resembled that seen after phenobarbital. Using an immunoblotting procedure and a radioimmunoassay, it was shown that the increase in cytochrome P-450 content in the liver after BCP treatment was, in part, due to an increase in the phenobarbital-inducible isozymes, P-450b + e. In the kidney, the increase in total cytochrome P-450 content after BCP exposure was not due to an increase in P-450b + e. The decrease in AHH activity appeared to be caused by noncompetitive inhibition of constitutive AHH activity by BCP. BCP also inhibited benzphetamine demethylation, although to a lesser extent. The failure to observe an increase in benzphetamine demethylase activity in vivo, despite the induction of P-450b, was probably due to the concomitant induction and inhibition of drug-metabolizing enzymes by BCP.