Binding and hydrolysis of meperidine by human liver carboxylesterase hCE-1.
Binding and hydrolysis of meperidine by human liver carboxylesterase hCE-1.
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发表时间：
1999-07
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通讯作者：
Jing Zhang;Joe C. Burnell;N. Dumaual;W. F. Bosron
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作者：
Jing Zhang;Joe C. Burnell;N. Dumaual;W. F. Bosron
人肝羧酸酯酶催化去脂类药物或异物酯水解成更易溶的酸和酒精产物以消除。两种羧酸酯酶，HCE-1和HCE-2已被提纯，并对它们在可卡因和海洛因水解中的作用进行了表征。用竞争结合分光光度法研究了度冷丁(杜冷丁)与丙氧酚(Darvon)的结合情况。HCE-1和HCE-2结合了这两种药物，KI值在0.4到1.3 mm范围内。HCE-1能将度冷丁分解为哌替酸和乙醇，而HCE-2则不能。HCE-1对度冷丁的Km值为1.9 mm，催化速率常数kcat为0.67min-1。HCE-1对度冷丁的水解性与其对含有简单脂肪醇取代基酯的水解性一致。因此，人肝微粒体中的HCE-1可能在度冷丁消除过程中起重要作用。丙氧酚不被HCE-1或HCE-2水解。这一观察结果与人类中丙氧酚代谢的主要水解途径的缺失是一致的。
Human liver carboxylesterases catalyze the hydrolysis of apolar drug or xenobiotic esters into more soluble acid and alcohol products for elimination. Two carboxylesterases, hCE-1 and hCE-2, have been purified and characterized with respect to their role in cocaine and heroin hydrolysis. The binding of meperidine (Demerol) and propoxyphene (Darvon) was examined in a competitive binding, spectrophotometric assay. The hCE-1 and hCE-2 bound both drugs, with Ki values in the 0.4- to 1.3-mM range. Meperidine was hydrolyzed to meperidinic acid and ethanol by hCE-1 but not hCE-2. The Km of hCE-1 for meperidine was 1.9 mM and the kcat (catalytic rate constant) was 0.67 min-1. Hydrolysis of meperidine by hCE-1 was consistent with its specificity for hydrolysis of esters containing simple aliphatic alcohol substituents. Hence, hCE-1 in human liver microsomes may play an important role in meperidine elimination. Propoxyphene was not hydrolyzed by hCE-1 or hCE-2. This observation is consistent with the absence of a major hydrolytic pathway for propoxyphene metabolism in humans.