Metabolism and toxicity of xenobiotics in the adrenal cortex, with particular reference to 7,12‐dimethylbenz(a) anthracene

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Abstract
The adrenal cortex contains high amounts of detoxifying enzymes, as well as generators and protectors of reactive oxygen species. The high content of cytochrome P‐450 enzymes in the adrenal cortex together with its remarkable tendency to accumulate hydrophobic substances probably contributes to the extraordinary vulnerability of the gland to a number of xenobiotics. The best studied adreno‐corticolytic compounds are the potent carcinogen 7, 12‐dimethylbenz(a)anthracene (DMBA) and its liver metabolite 7‐hydroxymethyl‐12‐methylbenz (a)anthracene (7‐OHM‐12‐MBA). Adrenocorticolysis generated by these agents in vivo as well as in vitro demonstrates high regioselective requirements and is strongly influenced by the presence of ACTH, steroids, cytochrome P‐450 inhibitors and antioxi‐dants. Furthermore, 7‐OHM‐12‐MBA has been demonstrated to uniquely generate selective and massive oxidation of mitochondrial glutathione in cultured rat adrenal cells. The DMBA‐induced adrenocorticolysis is thoroughly discussed in this review with particular emphasis on the metabolism of DMBA and the influence of various effectors. A working hypothesis involving a possible peroxidative mechanism is also presented.