Tumor necrosis factor alpha partially contributes to lipopolysaccharide-induced downregulation of CYP3A in fetal liver: its repression by a low dose LPS pretreatment

With embryonic development, fetal hepatocytes gradually express various types of cytochromes P450 (CYPs) that play a key role in the detoxification of xenobiotics. In the present study, we showed that maternal lipopolysaccharide (LPS) exposure downregulated cyp3a11 mRNA and CYP3A protein in fetal liver. The increased level of TNF-alpha protein in fetal liver, transferred from either the maternal circulation or amniotic fluid, seems to be associated with LPS-induced downregulation of cyp3a11 mRNA and CYP3A protein in fetal liver. Interestingly, a low dose LPS (10mug/kg) pretreatment attenuated LPS-induced downregulation of cyp3a11 mRNA and CYP3A protein in fetal liver. Correspondingly, a low dose LPS pretreatment attenuated LPS-induced downregulation of pregnane X receptor (pxr) in fetal liver. Additional experiment showed that a low dose LPS pretreatment decreased the level of TNF-alpha in maternal serum and amniotic fluid and counteracted LPS-induced expression of TNF-alpha mRNA in maternal liver and placenta. Although a low dose LPS pretreatment alleviated LPS-induced increase in TNF-alpha in fetal liver, it had little effect on TNF-alpha mRNA in fetal liver. These results suggest that a low dose LPS pretreatment protects fetuses against LPS-induced downregulation of hepatic cyp3a11 and pxr expression through the repression of maternally sourced TNF-alpha production.