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.
Highlights
All-trans-retinoic acid is the key active metabolite of vitamin A. atRA is a critical morphogen and a signaling molecule during embryonic and fetal development
The aims of this study were to determine whether CYP26 enzymes are important in atRA clearance in human fetal liver, whether CYP3A7 contributes to atRA clearance in human fetal liver and to determine the efficiency of the fetal liver in eliminating atRA that passes to the fetus from maternal circulation
We hypothesized that a barrier, such as the fetal liver or the placenta, exists between the mother and the fetus to prevent maternal endogenous atRA passing to the fetus and enabling autonomous regulation of fetal atRA concentrations
Summary
All-trans-retinoic acid (atRA) is the key active metabolite of vitamin A (retinol). atRA is a critical morphogen and a signaling molecule during embryonic and fetal development. In the adult human liver, atRA has been shown to be mainly metabolized by CYP enzymes CYP26A1, CYP26B1, CYP3A and CYP2C813,14. CYP26A1 has been shown to be the main atRA hydroxylase likely regulating atRA clearance[13]. Www.nature.com/scientificreports human fetal organs is limited, and it is unknown whether the same CYP26 enzymes that appear predominant in metabolizing atRA in adult human liver regulate atRA clearance in the fetal liver. Based on the existing data that show the importance of CYP26 enzymes in atRA metabolism in adult liver and the importance of tight regulation of retinoid gradients in the developing fetus, we hypothesized that CYP26A1 plays an important role in fetal atRA clearance, and that the fetal liver limits maternal-fetal transfer of atRA. The aims of this study were to determine whether CYP26 enzymes are important in atRA clearance in human fetal liver, whether CYP3A7 contributes to atRA clearance in human fetal liver and to determine the efficiency of the fetal liver in eliminating atRA that passes to the fetus from maternal circulation
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