Mouse Cyp2c expression and zonation structure in the liver begins in the early neonatal stage

Abstract

In the adult liver, drug-metabolizing enzymes such as cytochrome P450 (CYP) efficiently metabolize drugs by forming an expression pattern called "zonation" structure around the central veins (CV). However, most previous studies on CYPs have focused on the expression levels of CYP mRNA and proteins in the whole liver. In this study, we analyzed not only the expression levels of Cyp2c family mRNAs and proteins in mice during fetal liver development, but also the relationship with their localization. In the whole fetal liver, Cyp2c mRNA and protein were hardly expressed. On the other hand, zonation analysis results showed that only some cells around the CV of the fetal liver expressed Cyp2c. In addition, the protein expression level of Cyp2c in the whole liver during the neonatal period started from postnatal day (P) 7 in both males and females, while the zonation was weakly formed from P5. This study suggested that fetal liver cannot metabolize Cyp2c substrate drugs transferred from mother to fetus due to the low expression of Cyp2c and unformed zonation. The expression level of Cyp2c protein in neonates was lower than that in adult liver, and the zonation structure was not clear, suggesting that drug metabolism was not sufficient. Furthermore, this study revealed that the expression level of Cyp2c does not correlate with the formation of zonation structures, because Cyp2c expression is found in hepatocytes near the CV even in the fetal and neonatal stages, when Cyp2c protein expression is hardly detectable in the whole liver.

Keywords: cytochrome P450; fetal liver; liver development; postnatal liver; zonation.