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.