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Vol. 28, Issue 3, 268-278, March 2000
Department of Pharmaceutical Sciences, St. Jude Children's
Research Hospital, Memphis, Tennessee (E.G.S., C.B., K.Y.); Deutsches
Krebsforschungszentrum, Heidelberg, Federal Republic of Germany (W.S.,
G.S.); Division of Analytical Biochemistry, Faculty of Pharmaceutical
Sciences, Hokkaido University, Kitaku, Sapporo, Hokkaido, Japan (T.K.);
Department of Cellular and Molecular Pharmacology, University of
California, San Francisco, California (L.B.); and Baker Medical
Research Institute, Melbourne, Australia (K.M., T.J.C.)
Cytochrome P-4503A, CYP2B, and P-450 reductase are induced
by glucocorticoids, antiglucocorticoids such as pregnenolone
16
-carbonitrile, and drugs such as rifampin and phenobarbital.
Although the pregnane X receptor is reported to mediate steroid and
drug activation of CYP3A via a conserved cis-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 glucocorticoid receptor in expression of
CYP3A and CYP2B, we compared the induction of these proteins in the
livers of normal mice and mice with a targeted mutation in the
glucocorticoid receptor. Mice lacking the glucocorticoid receptor show
no difference in constitutive hepatic expression of CYP3A but show a
decrease in the level of CYP2B. Glucocorticoid receptor-deficient mice
challenged with either dexamethasone or pregnenolone 16-carbonitrile
failed to induce CYP2B proteins, whereas CYP2B was readily induced in
(+/+) mice. In contrast, CYP3A and P-450 reductase proteins were
induced by either 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 aminotransferase in mice regardless of
glucocorticoid receptor genotype, and rifampin did not compete for
ligand binding to either mouse or human glucocorticoid receptor. Phenobarbital induced CYP3A, CYP2B, and P-450 reductase in all mice,
but the amplitude of induction was diminished 37% in glucocorticoid receptor-null mice. Thus, there are distinctly different essential requirements of CYP3A, CYP2B, and P-450
reductase genes for the glucocorticoid receptor in their
induction by steroids and drugs.
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