Induction of cytochrome P4503A by the antiglucocorticoid mifepristone and a novel hypocholesterolaemic drug.
Rat liver microsomal testosterone (250 microM) hydroxylation and immunoreactive CYP3A protein were compared after administration of the antiglucocorticoid RU 486 (50 mg.kg-1.day-1 for 4 days) and the hypocholesterolaemic drug SR-12813 (150 mg.kg-1.day-1 for 4 days). Markers of CYP3A-mediated enzyme activity (testosterone 15 beta-, 6 beta-, and 2 beta-hydroxylation) were increased after administration of both drugs. Testosterone 6 beta-hydroxylation was increased 5-fold by RU 486 and 9-fold by SR-12813. Administration of dexamethasone alone at 150 mg.kg-1.day-1 or in combination with RU 486 induced testosterone 6 beta-hydroxylation 15- to 20-fold. The lack of antagonistic effect of RU 486 on dexamethasone-mediated CYP3A induction strengthens support for the hypothesis that the "classical glucocorticoid receptor" does not play a part in this process. The induction of CYP3A enzymes by the bisphosphonate SR-12813 suggests the existence of a new class of compounds with CYP3A inducing properties.
Williams
J A
JA
Department of Medicine, University of Aberdeen, UK.
Chenery
R J
RJ
Berkhout
T A
TA
Hawksworth
G M
GM
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D001189:Aryl Hydrocarbon Hydroxylases; D015153:Blotting, Western; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004164:Diphosphonates / Q000494:pharmacology*; D004790:Enzyme Induction; D005260:Female; D006727:Hormone Antagonists / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D015735:Mifepristone / Q000494:pharmacology*; D010089:Oxidoreductases, N-Demethylating / Q000096:biosynthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013739:Testosterone / Q000378:metabolism
D000924:Anticholesteremic Agents; D004164:Diphosphonates; D006727:Hormone Antagonists; C100355:SR 12813; D015735:Mifepristone; D013739:Testosterone; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating