Growth hormone determines sexual dimorphism of hepatic cytochrome P450 3A4 expression in transgenic mice
Growth hormone determines sexual dimorphism of hepatic cytochrome P450 3A4 expression in transgenic mice
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DOI：
10.1124/jpet.105.094367
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发表时间：
2006-03-01
影响因子：
3.5
通讯作者：
Gonzalez, FJ
中科院分区：
文献类型：
--
作者：
Cheung, C;Yu, AM;Gonzalez, FJ
最近，在一个携带人细胞色素P450 3A4基因的转基因小鼠中，研究了年龄和性别对肝脏细胞色素P450 3A4表达的影响。为了进一步研究人类细胞色素P3A基因的生理调控，利用同时含有细胞色素P3A4和细胞色素P3A7基因的细菌人工染色体克隆，建立了一种新的转基因小鼠系。在转基因小鼠胎肝中观察到了CYP3A7的表达，而在青春期后的小鼠胎肝中观察到了以性别二态为特征的发育性表达。肝脏细胞色素P3A4蛋白和RNA在未成熟转基因雄性小鼠中表达，6周龄后检测不到，而未成熟雌性小鼠和成年雌性小鼠肝脏中均有表达。异种受体激活剂苯巴比妥显著升高了雄性和雌性肝脏中的CYP3A4，表明药物诱导了该小鼠模型中的CYP3A4转基因。此外，在转基因雄性小鼠中持续输注重组生长激素(GH)，覆盖了雄性血浆GH谱的脉动性，使肝脏CYP3A4的mRNA和蛋白增加到正常雌性水平。持续的生长激素治疗也使内源性小鼠Cyp2b和Cyp3a44基因的表达女性化。因此，人类的CYP3A4包含了所有必需的基因调控序列，以响应发育表达和性二态的内源性激素调节，特别是生长激素。这些发现可能有助于阐明GH在人类肝脏中的性别依赖性表达中的作用，并提示GH治疗可能改变CYP3A4底物的药代动力学和药效学性质，导致男性体内药物代谢和处置的增强。
The impact of age and sex on the expression of hepatic cytochrome P450 3A4 (CYP3A4) was recently determined in a transgenic mouse line carrying the human CYP3A4 gene. To further investigate the physiological regulation of human CYP3A genes, a novel transgenic mouse line was generated using a bacterial artificial chromosome clone containing both CYP3A4 and CYP3A7 genes. CYP3A7 expression was observed in transgenic mouse fetal livers, whereas CYP3A4 exhibited developmental expression characterized by sexual dimorphism in postpubertal livers. Hepatic CYP3A4 protein and RNA were expressed in immature transgenic male mice and became undetectable after 6 weeks of age, whereas CYP3A4 was expressed in both immature and adult females. CYP3A4 was markedly elevated by the xenobiotic receptor activator phenobarbital in both male and female livers, demonstrating drug induction of the CYP3A4 transgene in this mouse model. Furthermore, continuous infusion of recombinant growth hormone (GH) in transgenic male mice, overriding the pulsatile male plasma GH profile, increased hepatic CYP3A4 mRNA and protein to normal female levels. Continuous GH treatment also feminized the expression of endogenous murine Cyp2b and Cyp3a44 genes. Thus, human CYP3A4 contains all of the gene regulatory sequences required for it to respond to endogenous hormonal regulators of developmental expression and sexual dimorphism, in particular GH. These findings may help elucidate the role of GH in determining the sex-dependent expression of CYP3A4 in human liver and suggest that GH therapy may alter the pharmacokinetic and pharmacodynamic properties of CYP3A4 substrates, leading to enhanced metabolism and disposition of drugs in men.