title: 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 alpha-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 beta-carbon leads to an adrenalytic effect, whereas hydroxylation at the alpha-carbon would represent an alternate deactivation pathway.
authors.affiliation: College of Pharmacy, University of Michigan, Ann Arbor 48109, USA.
authors.forename: W
authors.initials: W
authors.lastname: Cai
authors.forename: R
authors.initials: R
authors.lastname: Benitez
authors.forename: R E
authors.initials: RE
authors.lastname: Counsell
authors.forename: T
authors.initials: T
authors.lastname: Djanegara
authors.forename: D E
authors.initials: DE
authors.lastname: Schteingart
authors.forename: J E
authors.initials: JE
authors.lastname: Sinsheimer
authors.forename: L L
authors.initials: LL
authors.lastname: Wotring
mesh_terms: D000302:Adrenal Cortex / Q000378:metabolism*; D000818:Animals; D001711:Biotransformation; D002417:Cattle; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line / Q000187:drug effects; D006854:Hydrocortisone / Q000032:analysis; D066298:In Vitro Techniques; D007536:Isomerism; D008939:Mitotane / Q000031:analogs & derivatives / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D008939:Mitotane; D006854:Hydrocortisone