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.
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000378:metabolism* / Q000633:toxicity; D000311:Adrenal Glands / Q000187:drug effects / Q000378:metabolism*; D000324:Adrenocorticotropic Hormone / Q000494:pharmacology; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000032:analysis; D001551:Benz(a)Anthracenes / Q000378:metabolism*; D003345:Corticosterone / Q000096:biosynthesis; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains
D001551:Benz(a)Anthracenes; D015127:9,10-Dimethyl-1,2-benzanthracene; D000324:Adrenocorticotropic Hormone; D001189:Aryl Hydrocarbon Hydroxylases; D003345:Corticosterone