Different expression mechanism of CYP2B subfamilies by phenobarbital and glucocorticoid hormone

研究了Cyp2b9和Cyp2b10基因在成年小鼠肾脏和肝脏中的表达。雌性小鼠肾脏中CYP2B mRNA的组成表达水平高于雄性小鼠，因为雌性小鼠肝脏中CYP2B9的表达量高于CYP2B10，雄性小鼠肝脏中CYP2B10的表达量高于雌性小鼠。用地塞米松（Dex）治疗后，雄性小鼠肾脏中CYP2B10的诱导量远远大于雌性小鼠。与右美托咪唑相比，苯巴比妥（PB）、孕烯醇酮-16α-碳腈（PCN）和1,1,1-三氯-，2-双（对氯苯基）乙烷（DDT）在两性肾脏中均未诱导Cyp2b基因的表达。在肝脏中，PB、PCN和DDT对两性CYP2B9和CYP2B10均有相同程度的诱导作用，而Dex仅诱导CYP2B10，同时抑制CYP2B9。糖皮质激素受体拮抗剂RU-486可降低雄性小鼠肾脏和肝脏中CYP2B mRNA的dex诱导表达。而RU-486本身更能诱导CYP2B mRNA的表达。性腺切除术增加了未治疗男性肝脏中CYP2B mRNA的表达，但抑制了两性肾脏中dex诱导的表达。这些观察结果表明：(a) Cyp2b基因的表达有多种调控途径，Dex使用的一条途径是通过糖皮质激素受体介导的，这与PB使用的途径不同；(b)性激素在小鼠Cyp2b基因的性别依赖性表达中起调节作用。此外，在青春期前小鼠肝脏中，CYP2B mRNA的组成表达是性别无关的，CYP2B9是主要亚型。在成熟阶段，CYP2B10在两性中表达，而CYP2B9在雄性中明显减少，导致成年小鼠的两性二态表达。垂体切除术通过显著增加雄性CYP2B9和CYP2B10的表达至与雌性相似的水平，消除了小鼠CYP2B亚家族的性别二态性。少

The expression of Cyp2b9 and Cyp2b10 genes was investigated in kidney and liver of adult mice. The constitutive expression level of CYP2B mRNA in kidney was higher in female than in male mice, as it was in the liver where more CYP2B9 than CYP2B10 was expressed in the females, and more CYP2B10 was expressed in the males. After treatment with dexamethasone (Dex), induction of CYP2B10 in the kidneys was far greater in male than in female mice. In contrast to Dex, phenobarbital (PB), pregnenolone-16α-carbonitrile (PCN), and 1,1,1-trichloro- ,2-bis(p-chlorophenyl)eihane (DDT) did not induce the expression of the Cyp2b gene in the kidneys of either sex. In the liver, PB, PCN, and DDT induced both CYP2B9 and CYP2B10 in both sexes to the same extent, whereas Dex induced only CYP2B10 and simultaneously suppressed CYP2B9. Dex-inducible expression of CYP2B mRNA was decreased by RU-486, an antagonist of glucocor-ticoid receptor, in both the kidneys and liver from male mice. However, RU-486 itself … More induced the expression of CYP2B mRNA. Gonadectomy increased the expression of CYP2B mRNA in untreated male liver, but suppressed Dex-induced expression in the kidneys of both sexes. These observations suggest that (a) there are multiple regulatory pathways in the expression of Cyp2b genes, one of which used by Dex is mediated via the glucocorticoid receptor, which is different from that used by PB, and (b) sex hormones play a role in the regulation of the sex-dependent expression of Cyp2b genes in the mouse.Furthermore, the constitutive expression of CYP2B mRNA in the livers of mice in the prepubertal stage was sex-independent, with CYP2B9 as the principal isoform. During the maturation stage, CYP2B10 was expressed in both sexes, whereas CYP2B9 was diminished markedly in the males, resulting in a sexually dimorphic expression in adult mice. Hypophysectomy eliminated the sexual dimorphism in the mouse CYP2B subfamily by markedly increasing the expression of both CYP2B9 and CYP2B10 in males to levels similar to those in females. Less