BOVINE ADRENAL-CORTEX TRANSFORMATIONS OF MITOTANE L)-1-(4-CHLOROPHENYL)-2,2-DICHLOROETHANE-O,P'-DDD] AND ITS P,P'-ISOMERS AND M,P'-ISOMERS

The adrenalytic activity of mitotane (o,p'-DDD) has made it useful in the treatment of adrenocortical carcinoma and Gushing's syndrome. In s upport of a study to develop mitotane analogs as more effective therap eutic agents and as a basis for understanding the toxicity of related compounds in the adrenals, the biotransformations of o,p'-DDD in adren ocortical homogenate preparations have been studied and compared with those of its m,p'- and p,p'-isomers. Aliphatic oxidation to the corres ponding acetic acid derivative, o,p'-, m,p'- or p,p'-DDA, was the majo r transformation for all the preparations. In the comparisons of the D DD isomers, the order of both DDA formation and apparent covalent bind ing was o,p'- > m,p'- > p,p'-DDD, There was also evidence for alpha-hy droxylation at the benzylic carbon with subsequent loss of water to fo rm ethylene derivatives. This was a minor pathway for o,p'-DDD, but wa s the major pathway for the other two isomers. Thus, while the total y ields of metabolites of o,p'- and m,p'-DDD were similar and at least t wice that of the p,p'-isomer, their distribution of metabolites differ ed significantly. The effects of the three isomers on cell growth and cortisol production with the human adrenocortical carcinoma cell line, NCI H-295, followed the same order as their DDA formation and tissue binding. It is proposed that hydroxylation by the adrenal cortex at th e beta-carbon leads to an adrenalytic effect, whereas hydroxylation at the alpha-carbon would represent an alternate deactivation pathway.