Effects of Diazepam,Phenobarbital,Propranolol,and Cimetidine on Diazepam Oxidizing Isoenzymes in Rat Liver Microsomes  

作　　者：匡唐永[1] 楼雅卿[1] 赵立安[1] 

机构地区：[1]北京医科大学药理系药物代谢研究室

出　　处：《Journal of Chinese Pharmaceutical Sciences》1997年第2期36-42,共7页中国药学（英文版）

摘　　要：Isolation and identification of the liver microsomal cytochrome P 450 isoen zymes responsible for the formation of diazepam main metabolites nordiazepam and temazepam in rats were studied. The effects of P 450 inducers and inhibitors on the protein contents in SDS poly acrylamide gel electrophoresis and thin layer chromatography to the corresponding diazepam me tabolizing activities of rat liver microsomes were observed. The P 450 contents were dramatically re duced by ip diazepam, cimetidine or propranolol. Diazepam and propranolol inhibited temazepam formation, high dose of propranolol also inhibited nordiazepam formation. Phenobarbital increased the P 450 contents and induced the production of both nordiazepam and temazepam. It also induced proteins with molecular weight (m) of 51 and 59 kDa in SDS PAGE and those with m ranging from 45 to 55 kDa and from 55 to 65 kDa in TLC. Propranolol inhibited both fractions, especially that of m 55～65 kDa, whereas diazepam tended to inhibit the fraction of 45～55 kDa. The protein of m 51 kDa could be mainly involved in diazepam C3 hydroxylation, whereas those of m 59 kDa could be responsible for the N demethylation of diazepam in rats.研究地西泮、苯巴比妥、普萘洛尔和西咪替丁对地西泮氧化代谢的影响及其药酶蛋白的初步分析，应用ＨＰＬＣ，ＳＤＳ聚丙烯酰胺凝胶电泳和薄层扫描测定地西泮及其代谢物，并对大鼠肝微粒体和酶蛋白进行分离和含量测定。结果表明地西泮、普萘洛尔和西咪替丁使肝微粒体中Ｐ４５０含量明显降低。地西泮和普萘洛尔明显抑制地西泮Ｃ３羟化活性，大剂量普萘洛尔尚能抑制地西泮Ｎ脱甲基。苯巴比妥明显诱导Ｐ４５０生成，增强地西泮Ｎ脱甲基和Ｃ３羟化酶活性及分子量为５１，０００和５９，０００的电泳蛋白带，而地西泮、普萘洛尔则呈抑制作用。并发现，地西泮Ｎ脱甲基酶活性和分子量为５９，０００蛋白含量呈线性相关（Ｐ＜０．０５），而Ｃ３羟化酶活性则与５１，０００蛋白含量呈线性相关（Ｐ＜０．０１）。因此地西泮Ｃ３羟化代谢可能与５１，０００的Ｐ４５０酶蛋白有关，而Ｎ脱甲基代谢则可能与５９，０００的Ｐ４５０酶蛋白有关。

关 键 词：DIAZEPAM Nordiazepam TEMAZEPAM Demethylase Hydroxylase Cyto  chrome P  450 Liver microsomes 

分 类 号：R9[医药卫生—药学]