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Cytochrome P450-Catalyzed Binding of 3-Methylsulfonyl-DDE and o,p'-DDD in Human Adrenal Zona Fasciculata/Reticularis

Department of Environmental Toxicology (Ö.L., I.B.), Uppsala University, Norbyvägen 18A, S-752 36 Uppsala, Sweden; and Endocrine Oncology Unit (B.S.), Department of Medical Sciences, University Hospital, S-751 85 Uppsala, Sweden

Address all correspondence and requests for reprints to: Dr. Ingvar Brandt, Department of Environmental Toxicology, Uppsala University, Norbyvägen 18 A, S-752 36 Uppsala, Sweden. E-mail . ingvar.brandt{at}ebc.uu.se

Abstract

3-Methylsulfonyl-2,2'-bis(4-chlorophenyl)-1,1'-dichloroethene (MeSO₂-DDE) is a potent, tissue-specific toxicant that induces necrosis of the adrenal zona fasciculata following a local CYP11B1-catalyzed activation to a reactive intermediate in mice. Autoradiography was used to examine CYP11B1-catalyzed binding of MeSO₂-[¹⁴C]DDE and the adrenocorticolytic drug 2-(2-chlorophenyl)-2-(4-chlorophenyl)-1,1-dichlorethane; (o,p'-[¹⁴C]DDD, Mitotane, Lysodren) in human adrenal tissue slice culture. Both compounds gave rise to a selective binding in the one sample of normal adrenal zona fasciculata/reticularis, leaving zona glomerulosa and the adrenal medulla devoid of binding. Addition of the CYP11B1 selective inhibitor metyrapone (50 µM) reduced MeSO₂-[¹⁴C]DDE binding below the detection limit, whereas o,p'-[¹⁴C]DDD binding was reduced only by 42%. Selective binding of MeSO₂-[¹⁴C]DDE and o,p'-[¹⁴C]DDD was also observed in an aldosterone-producing adrenocortical carcinoma and in a nonfunctional adrenocortical hyperplasia. Exposure of slices from the normal adrenal cortex to MeSO₂-DDE (25 µM) resulted in an increased accumulation of 11-deoxycorticosterone, 11-deoxycortisol and androstenedione in the medium, and exposure to o,p'-DDD (25 µM) did not alter the steroid secretion pattern. No histological changes were found in either MeSO₂-DDE- or o,p'-DDD-exposed slices, compared with nonexposed slices. We suggest that MeSO₂-DDE might act as a potent adrenocorticolytic agent in humans. Further studies are needed to establish the usefulness of MeSO₂-DDE as a possible alternative for the treatment of adrenocortical hypersecretion and tumor growth.

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