Ethylbenzene-mediated induction of cytochrome P450 isozymes in male and female rats.
Ethylbenzene-mediated induction of cytochrome P450 isozymes in male and female rats.
复制标题
乙苯介导的雄性和雌性大鼠细胞色素 P450 同工酶的诱导。
DOI：
10.1016/0006-2952(92)90382-s
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发表时间：
1992
影响因子：
5.8
通讯作者：
Backes,WL
中科院分区：
文献类型：
--
作者：
Sequeira,DJ;Eyer,CS;Cawley,GF;Nick,TG;Backes,WL
将雄性和雌性Holtzman大鼠暴露于氯吡格雷，并研究其对肝微粒体活性的影响。研究了碳氢化合物和性别对P450依赖的药物和芳烃代谢的影响。碳氢化合物处理产生了两种细胞色素P450依赖性活动的诱导模式：（1）两性共同诱导;（2）仅在雌性中诱导。在大鼠暴露于甲苯后，在两种性别中均诱导了苄非他明N-脱甲基化、7-乙氧基香豆素O-脱乙基化、对硝基苯甲醚O-脱甲基化和甲苯的芳香羟基化。甲基苯丙胺N-去甲基化率在女性中增加了4倍，在男性中增加了近一倍。在暴露于α-氨基丁酸后，雌性动物的7-乙氧基香豆素O-脱乙基化增加了3倍，雄性动物增加了一倍，而两种性别的对硝基苯甲醚O-脱甲基化增加了4倍。乙苯对甲苯芳香羟基化代谢产物的形成影响最大。在雌性和雄性大鼠中，乙苯暴露使邻甲酚形成率分别增加4倍和9倍。在暴露于碳氢化合物之前，对甲酚的形成率在两种性别中均无法检测到;然而，在给予大鼠乙基苯后，雌性大鼠的形成率增加至0.4 nmol/min/mg蛋白质，雄性大鼠的形成率增加至0.9 nmol/min/mg蛋白质。乙苯暴露选择性地诱导氨基比林脱甲基化，苯胺羟基化，N，N-二甲基亚硝胺N-脱甲基化（DMNA）和甲苯的脂肪族羟基化。氨基比林、苯胺和DMNA的速率比对照增加50%，而由甲苯形成苯甲醇的速率增加至对照的260%。Western免疫印迹表明，在雄性大鼠中，顺铂处理诱导细胞色素P450 2B 1/2B 2的程度更大，而在雌性大鼠中仅诱导细胞色素P450 2 E1。乙苯暴露对细胞色素P450 1A 1水平无明显影响。
Male and female Holtzman rats were exposed to ethylbenzene, and the effect on liver microsomal activities was studied. Hydrocarbon- and sex-dependent effects on P450-dependent metabolism of drugs and aromatic hydrocarbons were investigated. Hydrocarbon treatment produced two patterns of induction in cytochrome P450-dependent activities: (1) induction common to both sexes; and (2) induction exclusively in females. Benzphetamine N-demethylation, 7-ethoxycoumarin O-deethylation,p-nitroanisole O-demethylation and aromatic hydroxylation of toluene were induced in both sexes after rats were exposed to ethylbenzene. The rate of benzphetamine N-demethylation increased 4-fold in females and nearly doubled in males. The increase in O-deethylation of 7-ethoxy-coumarin was 3-fold in females and doubled in males, whilep-nitroanisole O-demethylation increased 4-fold in both sexes after exposure to ethylbenzene. Ethylbenzene had its greatest effect upon the formation of aromatic hydroxylated metabolites of toluene. Ethylbenzene exposure increased the rate ofo-cresol formation by 4- and 9-fold in female and male rats, respectively. The formation rate ofp-cresol was undetectable in either sex prior to hydrocarbon exposure; however, after the rats were given ethylbenzene, rates increased to 0.4 nmol/min/mg protein in females and to 0.9 nmol/min/mg protein in the males. Ethylbenzene exposure selectively induced aminopyrine demethylation, aniline hydroxylation,N,N-dimethylnitrosamine N-demethylation (DMNA) and aliphatic hydroxylation of toluene in females. Rates for aminopyrine, aniline, and DMNA were increased 50% over controls, while formation of benzyl alcohol from toluene was enhanced to 260% of control. Western immunoblotting indicated that ethylbenzene treatment induced cytochrome P450 2B1/2B2 to a greater extent in male rats and cytochrome P450 2E1 only in females. Ethylbenzene exposure did not affect significantly the level of cytochrome P450 1A1.