Potential role for human cytochrome P450 3A4 in estradiol homeostasis.
Potential role for human cytochrome P450 3A4 in estradiol homeostasis.
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DOI：
10.1210/en.2004-1248
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发表时间：
2005-07
期刊：
影响因子：
4.8
通讯作者：
A. Yu;K. Fukamachi;K. Krausz;C. Cheung;F. Gonzalez
中科院分区：
文献类型：
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作者：
A. Yu;K. Fukamachi;K. Krausz;C. Cheung;F. Gonzalez
此前，据报道，人类 CYP3A4 转基因 (Tg-CYP3A4) 小鼠系表现出小肠中表达的细胞色素 P450 3A4 (CYP3A4) 增强了咪达唑仑的代谢。在这里，我们表明 CYP3A4 以及小鼠 cyp3a 和 cyp2b 的表达均依赖于年龄和性别。 CYP3A4 在 2 周和 4 周龄的雄性和雌性 Tg-CYP3A4 小鼠的肝脏中表达。自 6 周起，CYP3A4 在男性肝脏中检测不到，而在女性肝脏中持续表达，但水平下降（3 至 5 倍）。孕烯醇酮16α-甲腈显着诱导肝脏CYP3A4表达，且女性中的水平高于男性。小鼠内在 cyp3a 和 cyp2b 的诱导也是性别依赖性的。 Tg-CYP3A4 雌性被发现缺乏泌乳能力，导致幼崽存活率显着降低。 Tg-CYP3A4哺乳期母亲的乳腺肺泡发育不全，乳汁含量低。此外，与野生型小鼠相比，Tg-CYP3A4 怀孕和哺乳小鼠乳腺中 β-酪蛋白和乳清酸性蛋白 mRNA 的表达水平明显较低。这种哺乳表型受损与 Tg-CYP3A4 小鼠血清雌二醇水平显着降低有关。药代动力学研究表明，与野生型小鼠相比，Tg-CYP3A4 小鼠静脉注射[(3)H]雌二醇的清除率显着增强。这些结果表明 CYP3A4 可能在雌二醇稳态中发挥重要作用。这对于孕妇和哺乳期妇女的治疗可能会引起关注，因为药物、补充剂、饮料和饮食中的 CYP3A4 抑制剂或诱导剂可能会改变 CYP3A4 基因表达和酶活性。
Previously, a human CYP3A4-transgenic (Tg-CYP3A4) mouse line was reported to exhibit enhanced metabolism of midazolam by cytochrome P450 3A4 (CYP3A4) expressed in small intestine. Here we show that expression of CYP3A4 and murine cyp3a and cyp2b was both age and sex dependent. CYP3A4 was expressed in the livers of male and female Tg-CYP3A4 mice at 2 and 4 wk of age. Since 6 wk, CYP3A4 was undetectable in male livers, whereas it was constitutively expressed in female livers at decreased levels (3- to 5-fold). Pregnenolone 16alpha-carbonitrile markedly induced hepatic CYP3A4 expression, and the level was higher in females than males. Induction of intrinsic murine cyp3a and cyp2b was also sex dependent. Tg-CYP3A4 females were found to be deficient in lactation, leading to a markedly lower pup survival. The mammary glands of the Tg-CYP3A4 lactating mothers had underdeveloped alveoli with low milk content. Furthermore, beta-casein and whey acidic protein mRNAs were expressed at markedly lower levels in Tg-CYP3A4 pregnant and nursing mouse mammary glands compared with wild-type mice. This impaired lactation phenotype was associated with significantly reduced serum estradiol levels in Tg-CYP3A4 mice. A pharmacokinetic study revealed that the clearance of iv administrated [(3)H]estradiol was markedly enhanced in Tg-CYP3A4 mice compared with wild-type mice. These results suggest that CYP3A4 may play an important role in estradiol homeostasis. This may be of concern for treatment of pregnant and lactating women because CYP3A4 gene expression and enzymatic activity can be potentially modified by CYP3A4 inhibitors or inducers in medications, supplements, beverages, and diet.