CYTOTOXICITY AND DECREASED CORTICOSTERONE PRODUCTION IN ADRENOCORTICAL CELLS BY METHYLSULPHONATED DERIVATIVES OF p,p′-DDE

3-methylsulphonyl-DDE (3-MeSO2-DDE) undergoes bioactivation by cytochrome P450 11B1 (CYP11B1) in the adrenal cortex of several animal species in vivo. The activated compound induces cell death in the adrenocortical zona fasciculata and decreases glucocorticoid production. We have in the present study reproduced both the cytotoxicity and the decreased hormone production in vitro using the mouse adrenocortical cell line Y-1. Cytotoxicity was inhibited by the CYP11-inhibitor etomidate, confirming that CYP11-dependent bioactivation takes place also in vitro. Moreover, 3-MeSO2-DDE decreased corticosterone production in a concentration-dependent manner both in cells that had been induced with forskolin and in non-induced cells. In addition, we have investigated the effects on cell viability and corticosterone production of three structurally related compounds. 2-MeSO2-DDE and 3,3′(bis)-MeSO2-DDE induced cytotoxicity, although to a lower degree than 3-MeSO2-DDE. In contrast, the parent compound p,p′-DDE was not cytotoxic, indicating that the methylsulphonyl moieties are required for biological activity. This study shows that by using the basic structures of 3-MeSO2-DDE in drug design we can easily screen for biologically active compounds in the development of new adrenocorticolytic drugs for adrenocortical cancer and Cushing’s syndrome. We consider the Y-1 and other adrenocortical cell lines to be useful tools in overcoming the gap between animal studies and estimation of potential therapeutic effects and/or risks in humans.