Macherey A C, Grégoire S, Tainturier G, Lhuguenot J C
Département de Biochimie et Toxicologie Alimentaires, Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation, Dijon, France.
Chirality. 1992;4(8):478-83. doi: 10.1002/chir.530040804.
The stereoselectivity of the peroxisome proliferation potency of 2-ethylhexanoic acid (2-EHA), a metabolite of the plasticizer di-(2-ethylhexyl) adipate, was investigated in vitro. The enantiomers of 2-EHA were prepared via the semipreparative HPLC resolution of their diastereoisomeric (+)-(R)-1-phenylethylamine derivatives and the subsequent hydrolytic cleavage. Monolayers of hepatocytes were incubated 3 days with solution of (-)-(R), (+)-(S), and (+/-)-2-EHA. The peroxisome proliferation potency was measured by means of determination of the peroxisomal palmitoyl coenzyme A oxidation. The theoretical induction component due to each enantiomer were calculated from the experimental data considering the enantiomeric purities of the acids. The (+)-(S)-enantiomer was found to be the most potent inducer e.g., the eutomer, while the (-)-(R) was the distomer. The eudismic ratio was about 1.6 and the racemic mixture exhibited an intermediary potency. These results, obtained in vitro in conditions avoiding confounding factors such as pharmacokinetics, suggest that the peroxisome proliferation induced by 2-ethylhexanoic acid is a stereoselective phenomenon.
对增塑剂己二酸二（2-乙基己基）酯的代谢产物2-乙基己酸（2-EHA）过氧化物酶体增殖能力的立体选择性进行了体外研究。2-EHA的对映体通过其非对映体（+）-（R）-1-苯乙胺衍生物的半制备高效液相色谱拆分及随后的水解裂解制备。将单层肝细胞与（-）-（R）、（+）-（S）和（+/-）-2-EHA溶液孵育3天。通过测定过氧化物酶体棕榈酰辅酶A氧化来测量过氧化物酶体增殖能力。根据实验数据，考虑到酸的对映体纯度，计算出每种对映体的理论诱导成分。发现（+）-（S）-对映体是最有效的诱导剂，即优映体，而（-）-（R）是劣映体。优效比约为1.6，外消旋混合物表现出中等效力。在避免药代动力学等混杂因素的体外条件下获得的这些结果表明，2-乙基己酸诱导的过氧化物酶体增殖是一种立体选择性现象。
