Chiral effects in adrenocorticolytic action of o,p'-DDD (mitotane) in human adrenal cells.
Adrenocortical carcinoma (ACC) is a rare malignant disease with poor prognosis. The main pharmacological choice, o,p'-DDD (mitotane), produces severe adverse effects. Since o,p'-DDD is a chiral molecule and stereoisomers frequently possess different pharmacokinetic and/or pharmacodynamic properties, we isolated the two o,p'-DDD enantiomers, (R)-(+)-o,p'-DDD and (S)-(-)-o,p'-DDD, and determined their absolute structures. The effects of each enantiomer on cell viability and on cortisol and dehydroepiandrosterone (DHEA) secretion in the human adrenocortical cell line H295R were assessed. We also assayed the o,p'-DDD racemate and the m,p'- and p,p'-isomers. The results show small but statistically significant differences in activity of the o,p'-DDD enantiomers for all parameters tested. The three DDD isomers were equally potent in decreasing cell viability, but p,p'-DDD affected hormone secretion slightly less than the o,p'- and m,p'-isomers. The small chiral differences in direct effects on target cells alone do not warrant single enantiomer administration, but might reach importance in conjunction with possible stereochemical effects on pharmacokinetic processes in vivo.
Asp
V
V
Environmental Toxicology, Uppsala University, Uppsala, Sweden.
Cantillana
T
T
Bergman
A
A
Brandt
I
I
D000302:Adrenal Cortex / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003687:Dehydroepiandrosterone / Q000378:metabolism; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism; D008939:Mitotane / Q000737:chemistry* / Q000494:pharmacology*; D013237:Stereoisomerism
D003687:Dehydroepiandrosterone; D008939:Mitotane; D006854:Hydrocortisone