Novel involvement of a mitochondrial steroid hydroxylase (P450c11) in xenobiotic metabolism.
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.
Lund
B O
BO
Department of Pharmacology and Toxicology, Swedish University of Agricultural Sciences, Uppsala.
Lund
J
J
D000302:Adrenal Cortex / Q000166:cytology / Q000201:enzymology; D000818:Animals; D002460:Cell Line; D019405:Cytochrome P-450 CYP11B2; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003633:Dichlorodiphenyl Dichloroethylene / Q000031:analogs & derivatives* / Q000378:metabolism; D008928:Mitochondria / Q000201:enzymology*; D013252:Steroid 11-beta-Hydroxylase / Q000378:metabolism*; D015262:Xenobiotics / Q000378:metabolism*
D015262:Xenobiotics; D003633:Dichlorodiphenyl Dichloroethylene; C055238:1-chloro-4-(2,2-dichloro-1-(4-chlorophenyl)ethenyl)-3-(methylsulfonyl)benzene; D003577:Cytochrome P-450 Enzyme System; D019405:Cytochrome P-450 CYP11B2; D013252:Steroid 11-beta-Hydroxylase