RNA Sequencing Reveals Age and Species Differences of Constitutive Androstane Receptor-Targeted Drug-Processing Genes in the Liver.

Abstract

The constitutive androstane receptor (CAR/Nr1i3) is an important xenobiotic-sensing nuclear receptor that is highly expressed in the liver and is well known to have species differences. During development, age-specific activation of CAR may lead to modified pharmacokinetics and toxicokinetics of drugs and environmental chemicals, leading to higher risks for adverse drug reactions in newborns and children. The goal of this study was to systematically investigate the age- and species-specific regulation of various drug-processing genes (DPGs) after neonatal or adult CAR activation in the livers of wild-type, CAR-null, and humanized CAR transgenic mice. At either 5 or 60 days of age, the three genotypes of mice were administered a species-appropriate CAR ligand or vehicle once daily for 4 days (i.p.). The majority of DPGs were differentially regulated by age and/or CAR activation. Thirty-six DPGs were commonly upregulated by CAR activation regardless of age or species of CAR. Although the cumulative mRNAs of uptake transporters were not readily altered by CAR, the cumulative phase I and phase II enzymes as well as efflux transporters were all increased after CAR activation in both species. In general, mouse CAR activation produced comparable or even greater fold increases of many DPGs in newborns than in adults; conversely, humanized CAR activation produced weaker induction in newborns than in adults. Western blotting and enzyme activity assays confirmed the age and species specificities of selected CAR-targeted DPGs. In conclusion, this study systematically compared the effect of age and species of CAR proteins on the regulation of DPGs in the liver and demonstrated that the regulation of xenobiotic biotransformation by CAR is profoundly modified by age and species.