Cytochrome P450-catalyzed binding of 3-methylsulfonyl-DDE and o,p'-DDD in human adrenal zona fasciculata/reticularis.
3-Methylsulfonyl-2,2'-bis(4-chlorophenyl)-1,1'-dichloroethene (MeSO(2)-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 MeSO(2)-[(14)C]DDE and the adrenocorticolytic drug 2-(2-chlorophenyl)-2-(4-chlorophenyl)-1,1-dichlorethane; (o,p'-[(14)C]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 microM) reduced MeSO(2)-[(14)C]DDE binding below the detection limit, whereas o,p'-[(14)C]DDD binding was reduced only by 42%. Selective binding of MeSO(2)-[(14)C]DDE and o,p'-[(14)C]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 MeSO(2)-DDE (25 microM) resulted in an increased accumulation of 11-deoxycorticosterone, 11-deoxycortisol and androstenedione in the medium, and exposure to o,p'-DDD (25 microM) did not alter the steroid secretion pattern. No histological changes were found in either MeSO(2)-DDE- or o,p'-DDD-exposed slices, compared with nonexposed slices. We suggest that MeSO(2)-DDE might act as a potent adrenocorticolytic agent in humans. Further studies are needed to establish the usefulness of MeSO(2)-DDE as a possible alternative for the treatment of adrenocortical hypersecretion and tumor growth.
Lindhe
Orjan
O
Department of Environmental Toxicology, Uppsala University, Norbyvägen 18A, S-752 36 Uppsala, Sweden.
Skogseid
Britt
B
Brandt
Ingvar
I
D000328:Adult; D001345:Autoradiography; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003633:Dichlorodiphenyl Dichloroethylene / Q000031:analogs & derivatives* / Q000378:metabolism*; D005260:Female; D006728:Hormones / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D008939:Mitotane / Q000378:metabolism*; D015383:Zona Fasciculata / Q000378:metabolism*; D015385:Zona Reticularis / Q000378:metabolism*
D006728:Hormones; D003633:Dichlorodiphenyl Dichloroethylene; C055238:1-chloro-4-(2,2-dichloro-1-(4-chlorophenyl)ethenyl)-3-(methylsulfonyl)benzene; D008939:Mitotane; D003577:Cytochrome P-450 Enzyme System