Chen J, Robertson G, Field J, Liddle C, Farrell G C
Department of Medicine, University of Sydney at Westmead Hospital, New South Wales, Australia.
Hepatology. 1998 Sep;28(3):624-30. doi: 10.1002/hep.510280304.
Gender differences in hepatic sex steroid and drug metabolism result from hormonal regulation of specific cytochrome P450 genes (CYP). In male rats, bile duct ligation (BDL) is associated with down-regulation of the male-specific genes, CYP2C11 and CYP3A2, together with a decrease in serum testosterone levels and a two- to three-fold increase in serum estradiol concentrations. We anticipated that if estrogen is responsible for down-regulation of male-specific CYPs in BDL male rats, the female-specific CYP2C12, which is not normally present in adult male rat liver, should be up-regulated. We examined this proposal by determining the profile of hepatic cytochrome P450 enzymes in female rats subjected to BDL, and by seeking evidence for expression of CYP2C12 in male rats that do not normally express this gene. In female rats killed 5 days after BDL, total cytochrome P450 content and NADPH-cytochrome P450-reductase (P450-reductase) were decreased to 74% and 58% of control, respectively. Microsomal enzyme activities attributable to CYP2A1, CYP2C6, and CYP2E1 were 50% to 60% of control, but ethylmorphine N-demethylase, which in female liver is catalyzed by CYP2C12 and to a lesser extent CYP2C6, was significantly less affected (81% of control). Likewise, levels of CYP2C6 and P450-reductase proteins were decreased in proportion to the corresponding enzyme activities (50% to 60%), while CYP2C12 protein (and mRNA levels) were not altered in BDL female rat liver. In sham-operated male rats, transcripts for CYP2C12 were rarely detected, but mRNA levels rose to appreciable levels within 24 hours of BDL, and CYP2C12 protein was expressed in hepatic microsomes of BDL male rats. Administration of estradiol to male rats produced a similar elevation of CYP2C12 mRNA, to values approximately 40% of female rats. It is concluded that CYP2C12 is up-regulated in male rats with cholestasis caused by BDL, while CYP2C12 protein is preserved in female rats when other microsomal proteins are decreased. These changes may be related to the increase in serum estradiol levels that result from altered hepatic steroid metabolism. The results demonstrate that activities of individual drug-metabolizing enzymes in liver disease can be determined by dysregulation of the constitutive expression of hepatic CYP genes.
肝脏中性别甾体和药物代谢的性别差异源于特定细胞色素P450基因（CYP）的激素调节。在雄性大鼠中，胆管结扎（BDL）与雄性特异性基因CYP2C11和CYP3A2的下调相关，同时血清睾酮水平降低，血清雌二醇浓度增加两到三倍。我们推测，如果雌激素是BDL雄性大鼠中雄性特异性CYP下调的原因，那么成年雄性大鼠肝脏中通常不存在的雌性特异性CYP2C12应该会上调。我们通过测定BDL雌性大鼠肝脏细胞色素P450酶的谱，以及寻找在正常情况下不表达该基因的雄性大鼠中CYP2C12表达的证据来检验这一假设。在BDL后5天处死的雌性大鼠中，总细胞色素P450含量和NADPH - 细胞色素P450还原酶（P450还原酶）分别降至对照的74%和58%。归因于CYP2A1、CYP2C6和CYP2E1的微粒体酶活性为对照的50%至60%，但在雌性肝脏中由CYP2C12催化且在较小程度上由CYP2C6催化的乙基吗啡N - 脱甲基酶受影响明显较小（为对照的81%）。同样，CYP2C6和P450还原酶蛋白水平与相应酶活性成比例降低（50%至60%），而BDL雌性大鼠肝脏中CYP2C12蛋白（和mRNA水平）未改变。在假手术的雄性大鼠中，很少检测到CYP2C12的转录本，但BDL后24小时内mRNA水平升至可观水平，并且BDL雄性大鼠肝脏微粒体中表达了CYP2C12蛋白。给雄性大鼠注射雌二醇导致CYP2C12 mRNA有类似升高，达到雌性大鼠值的约40%。结论是，在BDL引起胆汁淤积的雄性大鼠中CYP2C12上调，而在其他微粒体蛋白减少时雌性大鼠中CYP2C12蛋白得以保留。这些变化可能与肝脏甾体代谢改变导致的血清雌二醇水平升高有关。结果表明，肝脏疾病中个体药物代谢酶的活性可由肝脏CYP基因组成型表达的失调来决定。
