Abstract
Rat liver microsomal testosterone (250 μM) hydroxylation and immunoreactive CYP3A protein were compared after administration of the antiglucocorticoid RU 486 (50 mg·kg−1·day−1for 4 days) and the hypocholesterolaemic drug SR-12813 (150 mg·kg−1·day−1for 4 days). Markers of CYP3A-mediated enzyme activity (testosterone 15β-, 6β-, and 2β-hydroxylation) were increased after administration of both drugs. Testosterone 6β-hydroxylation was increased 5-fold by RU 486 and 9-fold by SR-12813. Administration of dexamethasone alone at 150 mg·kg−1·day−1or in combination with RU 486 induced testosterone 6β-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.
Footnotes
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Send reprint requests to: Dr. J. Andrew Williams, Section of Molecular Carcinogenesis, Haddow Laboratories, Institute of Cancer Research, Cotswold Road, Sutton SM2 5NG, UK.
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↵1 Present address : MRC EETU, St. George’s Hospital Medical School, Cranmer Terrace, London. SW17 ORE
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JAW is in receipt of an MRC-CASE Ph.D studentship in collaboration with SmithKline Beecham Pharmaceuticals.
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2 Abbreviations used are HRP, horseradish peroxidase; DAB, diaminobenzidine; HMG-CoA, 3-hydroxy-3-methylglutarate-CoA, ns = not significant
- Received November 27, 1996.
- Accepted February 11, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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