Potential role for human cytochrome P450 3A4 in estradiol homeostasis.
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.
Yu
Ai-Ming
AM
Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Fukamachi
Katsumi
K
Krausz
Kristopher W
KW
Cheung
Connie
C
Gonzalez
Frank J
FJ
D000375:Aging / Q000378:metabolism; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D002364:Caseins / Q000235:genetics; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004958:Estradiol / Q000378:metabolism*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006706:Homeostasis / Q000502:physiology*; D006801:Humans; D007774:Lactation / Q000235:genetics; D008099:Liver / Q000378:metabolism; D008297:Male; D008321:Mammary Glands, Animal / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D008894:Milk Proteins / Q000235:genetics; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism; D010641:Phenotype; D011285:Pregnenolone Carbonitrile / Q000494:pharmacology; D012737:Sex Factors; D019076:Transgenes
D002364:Caseins; D008894:Milk Proteins; C024471:whey acidic proteins; D011285:Pregnenolone Carbonitrile; D004958:Estradiol; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D010089:Oxidoreductases, N-Demethylating