Scaling in vitro activity of CYP3A7 suggests human fetal livers do not clear retinoic acid entering from maternal circulation

Abstract

All-trans-retinoic acid (atRA), the active metabolite of vitamin A, is a critical signaling molecule during embryonic and fetal development and is necessary for maternal health. Fetal exposure to endogenous atRA is tightly regulated during gestation in a tissue specific manner and maternal exposure to exogenous retinoids during pregnancy is teratogenic. The clearance of atRA is primarily mediated by the cytochrome P450 (CYP) 26 enzymes, which play an essential role in controlling retinoid gradients during organogenesis. We hypothesized that CYP26 enzymes in the human fetal liver also function as a protective barrier to prevent maternal atRA reaching fetal circulation. Using human fetal liver tissue, we found that the mRNA of CYP26A1 and CYP26B1 enzymes is expressed in the human fetal liver. However, based on inhibition studies, metabolite profiles and correlation of atRA metabolism with testosterone hydroxylation, clearance of atRA in the fetal livers was mediated by CYP3A7. Based on in vitro-to-in vivo scaling, atRA clearance in the fetal liver was quantitatively minimal, thus providing an insufficient maternal-fetal barrier for atRA exposure.