title: Induction of the cytochrome P450 3A subfamily in rat liver correlates with the binding of inducers to a microsomal protein.
abstract: The specific binding of the archetypal cytochrome P450 3A subfamily (CYP3A) inducer dexamethasone is examined in microsomal fractions since rat and human liver CYP3A is induced by glucocorticoids through a mechanism which is apparently independent of the cytosolic glucocorticoid receptor. Dexamethasone binds in a specific and saturable manner to microsomes with an affinity constant (Kd) of 59 +/- 12.9 nM which compares to a Kd of 2.3 +/- 0.17 nM in cytosol. The total receptor concentrations ([LR]emax) in microsomes and cytosol are 9.5 +/- 1.67 pmols/mg protein and 410 +/- 167 fmol/mg protein respectively. The microsomal binding of dexamethasone is antagonised by several transcriptional and/or post-transcriptional CYP3A inducers with decreasing potency pregnenolone 16 alpha carbonitrile > metyrapone > phenobarbitone. Troleandomycin, which indirectly induces CYP3A1 in vivo and by protein stabilisation, does not antagonise the binding of dexamethasone in microsomes. The transcriptional and/or post-transcriptional induction of CYP3A may therefore be associated with the interaction of inducers with a microsomal protein.
authors.affiliation: DH Department of Toxicology, St Bartholomew's Hospital Medical College, London, UK.
authors.forename: M C
authors.initials: MC
authors.lastname: Wright
authors.forename: A J
authors.initials: AJ
authors.lastname: Paine
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D001665:Binding Sites; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D003600:Cytosol / Q000378:metabolism; D003907:Dexamethasone / Q000378:metabolism*; D004790:Enzyme Induction / Q000187:drug effects; D006801:Humans; D007700:Kinetics; D008099:Liver / Q000378:metabolism*; D008297:Male; D008797:Metyrapone / Q000494:pharmacology; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D010089:Oxidoreductases, N-Demethylating / Q000096:biosynthesis*; D010634:Phenobarbital / Q000494:pharmacology; D011285:Pregnenolone Carbonitrile / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D014217:Troleandomycin / Q000494:pharmacology
chemical_list: D011965:Receptors, Glucocorticoid; D011285:Pregnenolone Carbonitrile; D003907:Dexamethasone; D003577:Cytochrome P-450 Enzyme System; D014217:Troleandomycin; D001189:Aryl Hydrocarbon Hydroxylases; C465138:Cyp3a23-3a1 protein, rat; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D010634:Phenobarbital; D008797:Metyrapone