The glucocorticoid receptor is essential for induction of cytochrome P-4502B by steroids but not for drug or steroid induction of CYP3A or P-450 reductase in mouse liver

Cytochrome P-4503A, CYP2B, and P-450 reductase are induced by glucocorticoi ds, antiglucocorticoids such as pregnenolone 16 alpha-carbonitrile, and dru gs such as rifampin and phenobarbital. Although the pregnane X receptor is reported to mediate steroid and drug activation of CYP3A via a conserved ci s-element in CYP3A genes, discrepancies exist between the induction of the endogenous CYP3A genes and the activation of the pregnane X receptor. It is a formal possibility that the glucocorticoid receptor may account for some of these discrepancies. To determine the requirement in vivo of the glucoc orticoid receptor in expression of CYP3A and CYP2B, we compared the inducti on of these proteins in the livers of normal mice and mice with a targeted mutation in the glucocorticoid receptor. Mice lacking the glucocorticoid re ceptor show no difference in constitutive hepatic expression of CYP3A but s how a decrease in the level of CYP2B. Glucocorticoid receptor-deficient mic e challenged with either dexamethasone or pregnenolone 16 alpha-carbonitril e failed to induce CYP2B proteins, whereas CYP2B was readily induced in (+/ +) mice. In contrast, CYP3A and P-450 reductase proteins were induced by ei ther inducer in wild-type and glucocorticoid receptor-null mice. Similarly, rifampin induced CYP3A in either wild-type or glucocorticoid receptor-null mice. Despite reports that rifampin is a nonsteroidal ligand for the human glucocorticoid receptor, rifampin failed to induce tyrosine aminotransfera se in mice regardless of glucocorticoid receptor genotype, and rifampin did not compete for ligand binding to either mouse or human glucocorticoid rec eptor. Phenobarbital induced CYP3A, CYP2B, and P-450 reductase in all mice, but the amplitude of induction was diminished 37% in glucocorticoid recept or-null mice. Thus, there are distinctly different essential requirements o f CYP3A, CYP2B, and P-450 reductase genes for the glucocorticoid receptor i n their induction by steroids and drugs.