Structure‐Activity Relationship for Inhibition of CYP11B1–Dependent Glucocorticoid Synthesis in Y1 Cells by Aryl Methyl Sulfones

Abstract

Abstract:The effects of xenobiotics on CYPl 1B1-dependent corticosterone synthesis (1 1 P-hydroxylase) in mouse adrenocortical Y 1 cells were studied. 3-Methylsulfonyl-2,2-bis(4-chlorophenyl)-l,l-dichloroethene (MeS02-DDE) and some methylsulfonyl polychlorinated biphenyls (MeS02-PCB) inhibited the corticosterone synthesis, whereas PCBs or DDE did not. This indicates a crucial role of the methyl sulfone group for this inhibitory effect. Kinetic analyses of MeS02-DDE and the two most potent MeS02-PCBs were conducted using Lineweaver-Burk double-reciprocal plots. The data showed a competitive inhibition of CYPlIB1 by the compounds, with apparent inhibitory constants (K,) of 1.6, 4.6, and 6.7 pM for MeS02-DDE, 4-MeS02-2,3,6,4'-tetrachlorobiphenyl, and 4-MeS02-2,3,6,3',4'-pentachlorobiphenyl, respectively. For comparison, the substrate K, was 3.5 pM in the cells, and metyrapone and ketoconazole had apparent K,-values of 0.8 and 0.04 pM, respectively. In contrast to all previously known inhibitors of CYPllBl, the aryl methyl sulfones are the first examples of CYPllB1 inhibitors not being heterocyclic amines or steroids. The aryl methyl sulfones are widespread environmental pollutants and their inhibition of CYPllBl constitutes another potential mechanism for endocrine disruption. Their influence on the synthesis of adrenocortical hormones thus merits further interest.

ATR‐101 inhibits cholesterol efflux and cortisol secretion by ATP‐binding cassette transporters, causing cytotoxic cholesterol accumulation in adrenocortical carcinoma cells

“…Most of these inhibitors reduced ATP depletion by ATR-101, suggesting that steroid accumulation contributed to ATR-101 cytotoxicity ( Figure 6A). The concentrations of the inhibitors that reduced ATP depletion by ATR-101 were consistent with their inhibitory coefficients for specific steroidogenic enzymes (Takahashi et al, 1990;Johansson et al, 1998;Garrido et al, 2014). The reduction of ATP depletion by ATR-101 when it was combined with any one of several different inhibitors of steroidogenesis is consistent with the hypothesis that steroid accumulation contributes to ATR-101 cytotoxicity.…”

Irreversible Binding and Adrenocorticolytic Activity of the DDT Metabolite 3-Methylsulfonyl-DDE Examined in Tissue-Slice Culture

“…The reduced corticosterone secretion in MeSO 2 -DDE-exposed slices may result from mitochondrial toxicity, but also from inhibition of CYP11B1 enzyme activity, as previously reported in adrenal Y1 cells (31,36). As demonstrated by electron microscopy, the mitochondrial membranes of zona fasciculata cells (the site of CYP11B1 localization) were vacuolated in the MeSO 2 -DDE treated slices.…”

“…CYP11B1 catalyzes the last step in this pathway but also, as mentioned, the metabolic activation of MeSO 2 -DDE in the adrenal zona fasciculata (12,30,31). Since tetracosactide stimulates both CYP11A1 and CYP11B1 activity (22,24,(32)(33)(34)(35), this peptide would be expected to increase both corticosterone synthesis and irreversible MeSO 2 -[ 14 C]DDE binding in the slice culture.…”

Disruption of glucocorticoid action by environmental chemicals: Potential mechanisms and relevance

“…Using human H295R and mouse Y1 adrenocortical cells it was shown that several persistent aryl methylsulfone metabolites of PCBs and DDT, including 3-methylsulfonyl-DDE, competitively inhibit mitochondrial 11␤-hydroxylase, which catalyzes the last step of glucocorticoid synthesis by converting 11-deoxycortisol to cortisol. Inhibition of 11␤-hydroxylase by 3-methylsulfonyl-DDE was comparable to that by the known drugs metyrapone and ketoconazole [49,50].…”