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.
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.
Cai
W
W
College of Pharmacy, University of Michigan, Ann Arbor 48109, USA.
Benitez
R
R
Counsell
R E
RE
Djanegara
T
T
Schteingart
D E
DE
Sinsheimer
J E
JE
Wotring
L L
LL
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
D008939:Mitotane; D006854:Hydrocortisone