The constitutive androstane receptor (CAR/Nr1i3) is an important xenobiotic-sensing nuclear receptor that is highly expressed in 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 (Li et al.) following neonatal or adult CAR activation in livers of wild-type (WT), CAR-null, and humanized CAR-transgenic (hCAR-TG) mice. At either 5- or 60-days of age, the 3 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, and they partitioned into 3 patterns: DPGs in Pattern-1 (up-regulated with age) and Pattern-2 (down-regulated with age) were predominantly regulated by age, whereas DPGs in Pattern 3 were predominantly regulated by CAR activation. There were 36 DPGs that were commonly up-regulated by CAR activation regardless of age or species of CAR; however, the fold-induction in the mRNA expression of these genes was profoundly modified by age. Although the cumulative mRNAs of uptake transporters were not readily altered by CAR, the cumulative Phase-I and -II enzymes as well as efflux transporters were all increased following CAR activation in both species. In general, mCAR activation produced comparable or even greater fold-increases of many DPGs in newborns than in adults; conversely, hCAR 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, neonatal livers appear to be more sensitive to CAR-activators, whereas hCAR and mCAR produce overlapping but not identical effects in hepatic DPG regulation.
- constitutive androstane receptor/CAR
- cytochrome P450
- gene regulation/transcription
- nuclear receptors
- The American Society for Pharmacology and Experimental Therapeutics