Influence of agents affecting monooxygenase activity on taurolithocholic acid-induced cholestasis.
In rats, pretreatment with certain ketones results in enhanced taurolithocholic acid (TLCA)-induced reduction in bile flow, whereas pretreatment with inhibitors of protein synthesis diminishes the effect on bile flow of cholestatic regimens. In the present study, the possible role of cytochrome P-450 in the ketone potentiation phenomenon was investigated. Male rats were pretreated with inducers or inhibitors of hepatic cytochrome P-450 and the impact of these pretreatments on TLCA-induced cholestasis assessed. Phenobarbital, 3-methylcholanthrene, chlordecone or mirex were used as inducers, and SKF 525-A, piperonyl butoxide, or cobaltous chloride as inhibitors of monooxygenase activity. Phenobarbital and 3-methylcholanthrene pretreatment enhanced TLCA-induced reduction of bile flow, while mirex and chlordecone were without effect. The three inhibitors of monooxygenase activity did not diminish TLCA-induced cholestasis. Instead, piperonyl butoxide and cobaltous chloride appeared to enhance the action of TLCA. Consequently, an increase in cytochrome P-450 (or specific isozymes) as a common denominator in the potentiation phenomenon appears unlikely. While hepatic proteins may play an important role in the potentiation of TLCA-induced cholestasis following pretreatment with ketones, the pattern of potentiation after pretreatment of rats with different inducers or inhibitors of cytochrome P-450 does not appear to implicate this family of proteins.
D000818:Animals; D001646:Bile / Q000187:drug effects / Q000502:physiology; D001835:Body Weight / Q000187:drug effects; D007631:Chlordecone / Q000633:toxicity; D002779:Cholestasis / Q000139:chemically induced*; D003035:Cobalt / Q000633:toxicity; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000378:metabolism*; D004357:Drug Synergism; D004790:Enzyme Induction; D007659:Ketones / Q000633:toxicity*; D008099:Liver / Q000187:drug effects*; D008297:Male; D008748:Methylcholanthrene / Q000633:toxicity; D008917:Mirex / Q000633:toxicity; D009929:Organ Size / Q000187:drug effects; D010634:Phenobarbital / Q000633:toxicity; D010882:Piperonyl Butoxide / Q000633:toxicity; D011335:Proadifen / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D013658:Taurolithocholic Acid / Q000633:toxicity*
D065607:Cytochrome P-450 Enzyme Inhibitors; D007659:Ketones; D003035:Cobalt; D013658:Taurolithocholic Acid; D008748:Methylcholanthrene; D003577:Cytochrome P-450 Enzyme System; D011335:Proadifen; C018021:cobaltous chloride; D010882:Piperonyl Butoxide; D007631:Chlordecone; D010634:Phenobarbital; D008917:Mirex