Induction of cytochrome P4503A by the antiglucocorticoid mifepristone and a novel hypocholesterolaemic drug

J. Andrew Williams; Richard J. Chenery; Theo Berkhout; Gabrielle M. Hawksworth

Induction of cytochrome P4503A by the antiglucocorticoid mifepristone and a novel hypocholesterolaemic drug

J. Andrew Williams, Richard J. Chenery, Theo Berkhout, Gabrielle M. Hawksworth

School of Life and Medical Sciences

Research output: Contribution to journal › Article › peer-review

11 Citations (Scopus)

Abstract

Rat liver microsomal testosterone (250μM) 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 15β-₁ 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^- ¹ or 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.

Original language	English
Pages (from-to)	757-761
Number of pages	5
Journal	Drug Metabolism and Disposition
Volume	25
Issue number	6
Publication status	Published - 1 Jun 1997

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title = "Induction of cytochrome P4503A by the antiglucocorticoid mifepristone and a novel hypocholesterolaemic drug",

abstract = "Rat liver microsomal testosterone (250μM) 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 15β-1 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- 1 or 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.",

author = "Williams, {J. Andrew} and Chenery, {Richard J.} and Theo Berkhout and Hawksworth, {Gabrielle M.}",

year = "1997",

month = jun,

day = "1",

language = "English",

volume = "25",

pages = "757--761",

journal = "Drug Metabolism and Disposition",

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publisher = "American Society for Pharmacology and Experimental Therapeutics",

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TY - JOUR

T1 - Induction of cytochrome P4503A by the antiglucocorticoid mifepristone and a novel hypocholesterolaemic drug

AU - Williams, J. Andrew

AU - Chenery, Richard J.

AU - Berkhout, Theo

AU - Hawksworth, Gabrielle M.

PY - 1997/6/1

Y1 - 1997/6/1

N2 - Rat liver microsomal testosterone (250μM) 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 15β-1 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- 1 or 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.

AB - Rat liver microsomal testosterone (250μM) 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 15β-1 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- 1 or 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.

M3 - Article

C2 - 9193879

AN - SCOPUS:0030987376

SN - 0090-9556

VL - 25

SP - 757

EP - 761

JO - Drug Metabolism and Disposition

JF - Drug Metabolism and Disposition

IS - 6

ER -

Induction of cytochrome P4503A by the antiglucocorticoid mifepristone and a novel hypocholesterolaemic drug

Abstract

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