Dahlström-King L, Couture J, Plaa G L
Département de pharmacologie, Faculté de médecine, Université de Montréal, Québec, Canada.
Toxicol Lett. 1992 Dec;63(3):243-52. doi: 10.1016/0378-4274(92)90087-z.
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.
在大鼠中，用某些酮进行预处理会导致牛磺石胆酸（TLCA）诱导的胆汁流量减少加剧，而用蛋白质合成抑制剂进行预处理则会减弱胆汁淤积方案对胆汁流量的影响。在本研究中，研究了细胞色素P - 450在酮增强现象中的可能作用。对雄性大鼠用肝细胞色素P - 450的诱导剂或抑制剂进行预处理，并评估这些预处理对TLCA诱导的胆汁淤积的影响。苯巴比妥、3 - 甲基胆蒽、十氯酮或灭蚁灵用作诱导剂，而SKF 525 - A、胡椒基丁醚或氯化钴用作单加氧酶活性的抑制剂。苯巴比妥和3 - 甲基胆蒽预处理增强了TLCA诱导的胆汁流量减少，而灭蚁灵和十氯酮则无作用。三种单加氧酶活性抑制剂并未减弱TLCA诱导的胆汁淤积。相反，胡椒基丁醚和氯化钴似乎增强了TLCA的作用。因此，细胞色素P - 450（或特定同工酶）作为增强现象的共同特征而增加似乎不太可能。虽然肝蛋白可能在酮预处理后TLCA诱导的胆汁淤积增强中起重要作用，但用不同的细胞色素P - 450诱导剂或抑制剂对大鼠进行预处理后的增强模式似乎并不涉及这一族蛋白。
