Novel Involvement of a Mitochondrial Steroid Hydroxylase (P450c11) in Xenobiotic Metabolism

doi:10.1074/jbc.270.36.20895

Novel Involvement of a Mitochondrial Steroid Hydroxylase (P450c11) in Xenobiotic Metabolism (*)

Bert-Ove Lund(1)(§) and
Johan Lund(2)

From the (1)Department of Pharmacology and Toxicology, Swedish University of Agricultural Sciences, Uppsala Biomedical Centre, Box 573, S-75123 Uppsala, and
(2) Department of Medical Nutrition, Karolinska Institutet, Huddinge University Hospital F60, NOVUM, S-14186 Huddinge, Sweden

^§ To whom correspondence should be addressed. Tel.: 46-18-174509; Fax: 46-18-504144.

Abstract

Adrenocortical mitochondrial cytochrome P450 isozymes of the Cyp11 family normally synthesize steroids with a very strict substrate specificity. However, for the first time, P450c11 was additionally shown to metabolize and bioactivate the adrenotoxic environmental pollutant 3-methylsulfonyl-2,2-bis(4-chlorophenyl)-1,1-dichloroethene (MeSO²-DDE). This conclusion is based on a striking correlation between inductions of MeSO²-DDE and deoxycorticosterone metabolism by forskolin in the adrenocortical cell lines Y1 and Kin-8, inhibition of P450c11-dependent activities in Y1 cells by MeSO²-DDE, and metabolism of MeSO²-DDE by non-steroidogenic COS cells after transfection with a cDNA encoding P450c11. The interaction between xenobiotics and glucocorticoid synthesis should focus more attention to xenobiotic-induced hormonal disturbances.

Footnotes

↵* This work was supported by the Swedish Environment Protection Board, the Swedish OK Environmental Research Foundation, and Grant K-KU-06542-304 from the Swedish Natural Science Research Council. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore by hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
↵1 The abbreviations used are:

MeSO²-DDE

3-methylsulfonyl-2,2-bis(4-chlorophenyl)-1,1-dichloroethene

DDT

2,2-bis(4-chlorophenyl)-1,1,1-trichloroethane

DDE

2,2-bis(4-chlorophenyl)-1,1-dichloroethene

P450

cytochrome P450

P450c11

11β-hydroxylase

P450scc

cholesterol side-chain cleavage enzyme

P450aldo

aldosterone synthase

HPLC

high performance liquid chromatography

ADX

adrenodoxin.
- Received June 5, 1995.
- Revision received July 17, 1995.