MeSO2-DDE (3-methylsulfonyl-2,2-bis(4-chloro-[14C]phenyl)-1,1-dichloroethene MeSO2-[14C]DDE)
MeSO2-DDE is a synthetic compound derived from DDE and aryl methyl sulfones. MeSO2-DDE is selectively taken up and covalently bound in the zona fasciculata in adrenal cortex in mice [74]. MeSO2-DDE is a potent adrenocorticolytic agent at the lower doses than mitotane in humans [34]. Similar to mitotane, MeSO2-DDE generated a reactive intermediate metabolite by binding to CYP11B1, mitochondrial degeneration, and cell death in the murine adrenal cortex [34]. In murine adrenocortical Y-1 tumor cells, both mitotane and MeSO2-DDE inhibited corticosterone production, but only MeSO2-DDE was cytotoxic. The cytotoxicity was inhibited by the potent CYP11B1 inhibitor etomidate, suggesting that CYP11B1 plays a role in this effect of MeSO2-DDE [75,76]. In addition, MeSO2-DDE inhibited cortisol production in H295R cells, but did not affect aldosterone secretion [77]. On the other hand, in H295R cells (5–15 µM) and in a nude mice xenograft model (50 mg kg-1, i.p.), mitotane was more cytotoxic than MeSO2-DDE [78]. The concentration and dose of MeSO2-DDE are important factors since at low concentrations it can stimulate steroid production and CYP11B1 expression, and at higher concentrations it has the opposite effect [79]. Investigation using minipigs showed that the plasma, fat, and liver concentrations of MeSO2-DDE were, respectively, 2-, 25-, and 18-fold higher than those of mitotane. Likewise, the rate of elimination was slow, and this might be a challenge to designing appropriate dosages for patients [76]. Overall, MeSO2-DDE may represent a potential alternative for the treatment of ACC, and further clinical studies are encouraged.