Toxicity of 7,12-dimethylbenz[a]anthracene and 7-hydroxymethyl-12-methylbenz[a]anthracene and its prevention in cultured rat adrenal cells. Evidence for a peroxidative mechanism of action.
The adrenocorticolytic agent DMBA and its liver metabolite, 7-OHM-12-MBA, were investigated with respect to their mechanism of toxicity in cultured rat adrenal cells. Under proper growth conditions both hydrocarbons caused a reproducible and ACTH-dependent inhibition of steroidogenesis and cell death, similar to the effects of these agents on the rat adrenal in vivo. The toxicity of both DMBA and 7-OHM-12-MBA was partially prevented by antioxidants suggesting a common peroxidative mechanism of action. Studies with cytochrome P-450 inhibitors showed that toxicity of DMBA, but not 7-OHM-12-MBA, required a cytochrome P-450-dependent metabolic activation in order to be toxic. In addition, metyrapone, an efficient and specific inhibitor of the mitochondrial 11 beta-hydroxylase, provided protection against DMBA-induced toxicity, which is in agreement with previous observations that adrenal necrosis caused by DMBA apparently originates in mitochondria. It is proposed that both 7-OHM-12-MBA and DMBA, the latter after metabolism to mainly phenols, act as pseudosubstrates for steroid hydroxylases and initiate peroxidative damage through hydroxylase-generated superoxide anion, and/or hydrogen peroxide. These results indicate that both adrenal and hepatic metabolism of DMBA are potentially important in DMBA-induced adrenocorticolysis in vivo.
Hallberg
E
E
Department of Biochemistry, Arrhenius Laboratory, University of Stockholm, Sweden.
Rydström
J
J
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000031:analogs & derivatives* / Q000633:toxicity*; D000302:Adrenal Cortex / Q000187:drug effects / Q000378:metabolism*; D000305:Adrenal Cortex Hormones / Q000096:biosynthesis; D000324:Adrenocorticotropic Hormone / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005260:Female; D007700:Kinetics; D051381:Rats; D011919:Rats, Inbred Strains
D000305:Adrenal Cortex Hormones; D000975:Antioxidants; C018970:7-hydroxymethyl-12-methylbenz(a)anthracene; D015127:9,10-Dimethyl-1,2-benzanthracene; D000324:Adrenocorticotropic Hormone; D003577:Cytochrome P-450 Enzyme System