Expression and Regulation of Human Fetal-Specific CYP3A7 in Mice

Abstract

CYP3A7 is the predominant cytochrome P450 (CYP) expressed in human fetal liver, accounting for 30-50% of the total CYP in fetal liver and 87-100% of total fetal hepatic CYP3A content. However, the lack of a rodent model limits the investigation of CYP3A7 regulation and function. Hence, double-transgenic mice expressing human pregnane X receptor (PXR) and CYP3A4/7 (Tg3A4/7-hPXR) were used to investigate the regulation and function of CYP3A7. Expression of CYP3A7 was monitored in mice that ranged in age from 14.5-d-old embryos to 8.5-d-old newborns; expression of CYP3A7 mRNA was increased before birth in the embryos and decreased after birth in the newborns. This is consistent with the observed developmental regulation of CYP3A7 protein levels and CYP3A7-mediated dehydroepiandrosterone 16α-hydroxylase activities. This developmental flux is also in agreement with previous studies that have investigated the expression of CYP3A7 in developing human liver. The regulation of CYP3A7 was further studied using hepatoblasts from the Tg3A4/7-hPXR mice. Glucocorticoids, including dexamethasone, cortisol, corticosterone, and cortisone all induced the expression of CYP3A7 mRNA, whereas rifampicin, an activator of PXR and an inducer of CYP3A4 in adult liver, had no effect on CYP3A7 expression. Cell-based promoter luciferase and chromatin immunoprecipitation assays further confirmed glucocorticoid receptor-mediated control of the CYP3A7 promoter. These findings indicate that CYP3A7 is developmentally regulated in mouse liver primarily by glucocorticoids through the glucocorticoid receptor. The Tg3A4/7-hPXR mouse model could therefore potentially serve as a tool for investigating CYP3A7 regulation and function.