Bovine adrenal cortex transformations of mitotane [1-(2-chlorophenyl)-1-(4-chlorophenyl)-2,2-dichloroethane; o, p′-DDD] and its p, p′- and m, p′-isomers

Abstract

The adrenalytic activity of mitotane ( o, p′-DDD) has made it useful in the treatment of adrenocortical carcinoma and Cushing's syndrome. In support of a study to develop mitotane analogs as more effective therapeutic agents and as a basis for understanding the toxicity of related compounds in the adrenals, the biotransformations of o, p′-DDD in adrenocortical homogenate preparations have been studied and compared with those of its m, p′- and p, p′-isomers. Aliphatic oxidation to the corresponding acetic acid derivative, o, p′-, m, p′- or p, p′-DDA, was the major transformation for all the preparations. In the comparisons of the DDD isomers, the order of both DDA formation and apparent covalent binding was o, p′- > m, p′- > p, p′-DDD. There was also evidence for α-hydroxylation at the benzylic carbon with subsequent loss of water to form ethylene derivatives. This was a minor pathway for o, p′-DDD, but was the major pathway for the other two isomers. Thus, while the total yields of metabolites of o, p′- and m, p′-DDD were similar and at least twice that of the p, p′-isomer, their distribution of metabolites differed 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 the β-carbon leads to an adrenalytic effect, whereas hydroxylation at the α-carbon would represent an alternate deactivation pathway.