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

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Abstract

Abstract:

The effects of xenobiotics on CYP11B1-dependent corticosterone synthesis (11β-hydroxylase) in mouse adrenocortical Y1 cells were studied. 3-Methylsulfonyl-2,2-bis(4-chlorophenyl)-1,1-dichloroethene (MeSO2-DDE) and some methylsulfonyl polychlorinated biphenyls (MeSO2-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 MeSO2-DDE and the two most potent MeSO2-PCBs were conducted using Lineweaver-Burk double-reciprocal plots. The data showed a competitive inhibition of CYP11B1 by the compounds, with apparent inhibitory constants (Ki) of 1.6, 4.6, and 6.7 μM for MeSO2-DDE, 4-MeSO2-2,3,6,4′-tetrachlorobiphenyl, and 4-MeSO2-2,3,6,3′,4′-pentachlorobiphenyl, respectively. For comparison, the substrate Km was 3.5 μM in the cells, and metyrapone and ketoconazole had apparent Ki-values of 0.8 and 0.04 μM, respectively. In contrast to all previously known inhibitors of CYP11B1, the aryl methyl sulfones are the first examples of CYP11B1 inhibitors not being heterocyclic amines or steroids. The aryl methyl sulfones are widespread environmental pollutants and their inhibition of CYP11B1 constitutes another potential mechanism for endocrine disruption. Their influence on the synthesis of adrenocortical hormones thus merits further interest.

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