Novel involvement of a mitochondrial steroid hydroxylase (P450c11) in xenobiotic metabolism

Abstract

Adrenocortical mitochondrial cytochrome P450 isozymes of the Cyp11 family normally synthesize steroids with a very strict substrate specificity. However, for the first time, P450c11 was additionally shown to metabolize and bioactivate the adrenotoxic environmental pollutant 3-methylsulfonyl-2,2- bis(4-chlorophenyl)-1,1-dichloroethene (MeSO2-DDE). This conclusion is based on a striking correlation between inductions of MeSO2-DDE and deoxycorticosterone metabolism by forskolin in the adrenocortical cell lines Y1 and Kin-8, inhibition of P450c11-dependent activities in Y1 cells by MeSO2-DDE, and metabolism of MeSO2-DDE by non-steroidogenic COS cells after transfection with a cDNA encoding P450c11. The interaction between xenobiotics and glucocorticoid synthesis should focus more attention to xenobiotic-induced hormonal disturbances.