Chiral effects in adrenocorticolytic action of o,p′-DDD (mitotane) in human adrenal cells
Chiral effects in adrenocorticolytic action of o,p′-DDD (mitotane) in human adrenal cells
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DOI：
10.3109/00498250903470230
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发表时间：
2010-03-01
期刊：
影响因子：
1.8
通讯作者：
Brandt, I.
中科院分区：
文献类型：
--
作者：
Asp, V.;Cantillana, T.;Brandt, I.
1. 摘要肾上腺皮质癌是一种罕见的恶性疾病，预后较差。主要的药物选择，o,p'-DDD（米托坦），产生严重的不良反应。由于o，p'- ddd是一种手性分子，而立体异构体往往具有不同的药代动力学和/或药效学性质，因此我们分离了两种o，p'- ddd对映体(R)-(+)-o,p'- ddd和(S)-(-)-o,p'- ddd，并确定了它们的绝对结构。观察各对映体对人肾上腺皮质细胞系H295R细胞活力及皮质醇和脱氢表雄酮（DHEA）分泌的影响。我们还分析了o， p'- ddd外消旋体和m，p'-和p，p'-异构体。结果显示，o, p'-DDD对映体在所有测试参数中的活性差异很小，但具有统计学意义。三种DDD异构体对降低细胞活力的作用相同，但p， p'- DDD对激素分泌的影响略小于o，p'-和m，p'-异构体。单独对靶细胞直接作用的小手性差异不能保证单一对映体给药，但可能与体内药代动力学过程中可能的立体化学作用结合起来具有重要意义。
1. Adrenocortical carcinoma (ACC) is a rare malignant disease with poor prognosis. The main pharmacological choice, o,p'-DDD (mitotane), produces severe adverse effects.2. 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.3. 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.4. 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.5. 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.