STRUCTURE-ACTIVITY RELATIONSHIP FOR INHIBITION OF CYP11B1-DEPENDENT GLUCOCORTICOID SYNTHESIS IN Y1 CELLS BY ARYL METHYL SULFONES

The effects of xenobiotics on CYP11B1-dependent corticosterone synthes is (11 beta-hydroxylase) in mouse adrenocortical Y1 cells were studied . ulfonyl-2,2-bis(4-chlorophenyl)-1,1-dichloroethene (MeSO2-DDE) and s ome 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 wer e conducted using Lineweaver-Burk double-reciprocal plots. The data sh owed a competitive inhibition of CYP11B1 by the compounds, with appare nt inhibitory constants (K-i) of 1.6, 4.6, and 6.7 mu M for MeSO2-DDE, 4-MeSO2-2,3,6,4'-tetrachlorobiphenyl, and 4-MeSO2-2,3,6,3',4'-pentach lorobiphenyl, respectively. For comparison, the substrate K-m was 3.5 mu M in the cells, and metyrapone and ketoconazole had apparent K-i-va lues of 0.8 and 0.04 mu M, respectively In contrast to all previously known inhibitors of CYP11B1, the aryl methyl sulfones are the first ex amples 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 f or endocrine disruption. Their influence on the synthesis of adrenocor tical hormones thus merits further interest.