Metabolism and toxic effects of 7,12-dimethyl-benz[a]anthracene in isolated rat adrenal cells.

Isolated rat adrenal cells in tissue culture, showing ACTH-induced corticosterone synthesis, were used as a model system for the study of adrenal metabolism and toxicity of 7,12-dimethylbenz[a]anthracene (DMBA). DMBA was metabolized at a rate of 10 pmol/min/10(6) cells and with a Km of 0.5 microM. Metabolite patterns and sensitivity to various AHH inhibitors suggest the involvement of an epoxide intermediate. In agreement with this proposal DMBA metabolite(s) were bound to cellular protein at a rate which was related to the AHH activity. Adrenal AHH was found to be insensitive to ACTH during a period of 24 h. Using ACTH-induced corticosterone synthesis as an indicator of cell damage the hepatic metabolite 7-hydroxymethyl-12-methyl-benz[a]anthracene was shown to be significantly more toxic than the parent compound DMBA. It is concluded that DMBA-dependent adrenal damage in vivo is due mainly to the liver metabolite 7-hydroxymethyl-12-methyl-benz[a]anthracene (7-OHM-12-MBA), possibly after secondary metabolic activation in the adrenal.