Estrogen Regulation of the Cytochrome P450 3A Subfamily in Humans

Abstract

This study examines the possible role of estrogen in regulating the expression of the human CYP3A subfamily: CYP3A4, CYP3A5, CYP3A7, and CYP3A43. To accomplish this goal, mRNA was quantified from human livers and endometrial samples, and total CYP3A protein levels were evaluated by Western immunoblot analysis of the liver samples. The human endometrial samples were from premenopausal and postmenopausal women. The premenopausal endometrium was either in the proliferative or secretory phase, whereas for the postmenopausal endometrium samples, the women had been treated with either a placebo or estropipate, an estrogen substitute.After analyses, CYP3A4 mRNA was shown to have lower hepatic expression in females than in males. In the endometrium, CYP3A4 and CYP3A43 are down-regulated by estrogen, whereas CYP3A5 is expressed at higher levels during the secretory phase. CYP3A7 was not detected in the endometrium. In addition, the CYP3A subfamily showed increased mRNA expression in the liver as age increased. The expression levels of total CYP3A protein and total CYP3A mRNA showed good correlation. Despite apparent regulation of CYP3A4 mRNA expression by estrogen, the effects of estrogen may be overshadowed by additional regulators of gene expression.It is known that men and women do not respond equally to certain drugs administered for therapeutic relief (Harris et al., 1995); however, the reasons have yet to be fully identified and appear to be multifaceted. A variety of possibilities may contribute to therapeutic discordance, but a probable explanation is that estrogen directly or indirectly regulates a gene or genes responsible for the differences in response. Of the genes that could cause variations in drug response, a metabolizing enzyme would be a likely candidate. In particular, the cytochrome P450 (P450) superfamily is known for metabolizing a diverse set of substrates with the cytochrome P450 3A (CYP3A) subfamily metabolizing the most diverse range of substrates (Guengerich, 1999). It is possible that an estrogen-regulated P450 of the CYP3A subfamily contributes to the gender dimorphism exhibited in the drug response between women and men.

Sex Differences: A Resultant of an Evolutionary Pressure?

“…In spite of minor discrepancies due to the specie or the strain taken in consideration, all the studies carried out so far pointed to the fact that generally in the liver the sex-specific differences are related to genes encoding proteins relevant for fatty acid, steroid and lipid metabolic pathways, immune defense together with those essential for xenobiotic metabolism (sulfotransferases, oxidoreductases and several cytochrome P450 (Cyp450) (Gonzalez and Lee, 1996;Waxman and Holloway, 2009;Williams et al, 2004). Compared to males, fertile females had higher rates of hepatic FA uptake, esterification and VLDL-TG formation and output, and less FA oxidation (Kushlan et al, 1981;Soler-Argilaga et al, 1975).…”

“…For instance, in rodents during pregnancy estrogens and placental growth hormone increase the liver content of CYP3A, a protein subfamily that contributes to the metabolism of several waste products and the largest percentage of xenobiotics (Evans and Relling, 1999). Liver catabolism of xenobiotics is specie-specific, but a significant effect of pregnancy on drug pharmacokinetic is well reported also for humans (Anderson, 2005;Williams et al, 2004;Zhang et al, 2008).…”

Sex Differences of Drug-metabolizing Enzyme: Female Predominant Expression of Human and Mouse Cytochrome P450 3A Isoforms

“…20) A similar tendency observed in in vitro studies using human liver microsomes has been reported by other groups, [21][22][23][24] while studies that failed to detect female dominance have also been reported. [25][26][27][28] Assessment of CYP3A activity in vivo has been carried out by measuring the clearance of various CYP3A substrates. Although there are some conflicting results, the majority of studies suggest that women exhibit 20-50% faster clearance of CYP3A-metabolized drugs.…”

Characterization of the Expression and Activity of Carboxylesterases 1 and 2 from the Beagle Dog, Cynomolgus Monkey, and Human

“…Quantitative real-time polymerase chain reaction (PCR) was conducted as described previously (Williams et al, 2004) with the following exceptions. The instrument used for analysis was an ABI Prism 7900HT (Applied Biosystems, Foster City, CA), and the primer and probe sets were designed for multiplexing.…”