Strain Differences in the Induction of Cytochrome P450 3A1/3A2 and Nuclear Receptors in the Liver by Phenobarbital and Dexamethasone in Sprague-Dawley Rats and Dark Agouti Rats

Abstract

Strain differences in the induction of cytochrome P450 (CYP) affect drug actions and side effects. Strain differences in the induction of CYP are important to evaluate drug-drug interactions in CYPs. We clarified strain differences in the induction of CYP3A1/3A2 and nuclear receptors by evaluating mRNA levels and metabolic activities in Sprague-Dawley (SD) rats and Dark Agouti (DA) rats (models for extensive and poor metabolism of CYP2D6, respectively). To clarify strain differences in CYP levels, we examined nuclear receptors such as the constitutive androstane receptor (CAR) and pregnane X receptor, which regulate the transcription of CYPs and transporters. We investigated CYP3A inductions in the liver after repeated intraperitoneal injections of phenobarbital (PB) or dexamethasone (DEX) into SD rats and DA rats for 3d. mRNA levels of CYP and nuclear receptors were determined by real-time reverse transcriptase-polymerase chain reaction. Metabolic activities of CYP3A were also determined. Increased CYP3A mRNA levels were observed in both rat strains after treatment with PB or DEX compared with the respective rat strains treated with vehicle alone. Induction of CYP3A mRNAs by DEX was higher in SD rats than in DA rats, suggesting that SD rats could be more susceptible to DEX than DA rats. Inductions of CAR by PB differed between strains. The increase in mRNA levels and activity of CYP3A by PB in SD rats and DA rats were similar. However, there were strain differences in CYP3A1/3A2 inductions after DEX treatment.