LeBlanc G A, Sundseth S S, Weber G F, Waxman D J
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115.
Cancer Res. 1992 Feb 1;52(3):540-7.
Treatment of male rats with the anticancer drug cisplatin leads to feminization of the profile of cytochrome P-450 and other microsomal enzymes involved in steroid hormone and drug metabolism (G.A. LeBlanc, and D.J. Waxman, J. Biol. Chem., 263: 15732-15739, 1988). The present study uses the rat model to evaluate the differential effects of cisplatin treatment on liver microsomal enzymes between genders, and also examines whether the modulation of enzyme activities by cisplatin and its analogues involves changes in P-450 gene expression. While cisplatin treatment of male rats caused a severalfold increase in female-predominant hepatic enzymes, including testosterone 5 alpha-reductase and testosterone 7 alpha-hydroxylase (P-450 form 2A1), it partially decreased the expression of these enzymes in females. The reduced expression of these estrogen-dependent enzymes in females may derive from the loss of circulating estradiol that was shown to occur in response to cisplatin treatment. Analysis of mRNA levels of individual P-450 forms revealed that the effects of cisplatin on P-450-catalyzed steroid hydroxylase activities in both male and female rats are primarily operative through the drug's effects on P-450 mRNA expression. P-450-dependent cyclophosphamide activation was significantly compromised in male rats after cisplatin administration; however, this activity was not altered in cisplatin-treated females. This sex-dependent effect of cisplatin was due to its suppression of P-450 form 2C11, a male-specific P-450 that is a major contributor to microsomal cyclophosphamide bioactivation in male rat liver. The clinically active cisplatin analogue iproplatin elicited effects very similar to those of cisplatin, while carboplatin and transplatin did not have significant effects on hepatic P-450 expression. Together, these findings demonstrate that the response of rat liver to cisplatin-induced changes in hepatic P-450 enzyme profiles and cyclophosphamide bioactivation capacity differs between the sexes, and in addition, these effects can be minimized by use of carboplatin in place of cisplatin.
用抗癌药物顺铂处理雄性大鼠会导致细胞色素P - 450以及其他参与类固醇激素和药物代谢的微粒体酶的谱发生女性化（G.A.勒布朗和D.J.韦克斯曼，《生物化学杂志》，263: 15732 - 15739，1988年）。本研究使用大鼠模型来评估顺铂处理对不同性别的肝脏微粒体酶的差异影响，并且还研究顺铂及其类似物对酶活性的调节是否涉及P - 450基因表达的变化。虽然用顺铂处理雄性大鼠会使以女性为主的肝脏酶增加几倍，包括睾酮5α - 还原酶和睾酮7α - 羟化酶（P - 450形式2A1），但它会部分降低这些酶在雌性大鼠中的表达。雌性大鼠中这些雌激素依赖性酶表达的降低可能源于顺铂处理后循环雌二醇的丧失，这已被证明会发生。对各个P - 450形式的mRNA水平的分析表明，顺铂对雄性和雌性大鼠中P - 450催化的类固醇羟化酶活性的影响主要是通过药物对P - 450 mRNA表达的作用起作用。顺铂给药后，雄性大鼠中P - 450依赖性环磷酰胺激活显著受损；然而，在经顺铂处理的雌性大鼠中这种活性没有改变。顺铂的这种性别依赖性作用是由于它对P - 450形式2C11的抑制，P - 450形式2C11是雄性特异性的P - 450，是雄性大鼠肝脏中微粒体环磷酰胺生物激活的主要贡献者。临床上有活性的顺铂类似物异丙铂引起的效应与顺铂非常相似，而卡铂和反铂对肝脏P - 450表达没有显著影响。总之，这些发现表明大鼠肝脏对顺铂诱导的肝脏P - 450酶谱变化和环磷酰胺生物激活能力的反应在性别之间存在差异，此外，通过使用卡铂代替顺铂可以将这些影响最小化。
