Comparison of amphetamine metabolism using isolated hepatocytes from five species including human.
Comparison of amphetamine metabolism using isolated hepatocytes from five species including human.
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使用来自包括人类在内的五个物种的分离肝细胞对苯丙胺代谢进行比较。
DOI：
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发表时间：
1986
影响因子：
3.5
通讯作者：
C. Tyson
中科院分区：
文献类型：
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作者：
C. Green;S. LeValley;C. Tyson
使用来自大鼠、兔、狗、松鼠猴和人类肝脏的分离肝细胞悬液来研究安非他明 (AMP) 的代谢，这种药物在体内已证明其代谢存在物种依赖性差异。通过灌注整个肝脏或活检标本来分离肝细胞。一般来说，每个物种的肝细胞的代谢物谱与之前鉴定的尿液代谢物的谱相对应。大鼠肝细胞主要通过芳香族羟基化将 AMP 代谢为对羟基苯丙胺。兔肝细胞几乎完全将 AMP 转化为氧化脱氨途径的产物。其他三个物种的肝细胞的代谢是混合的，但在狗、松鼠猴和人类肝细胞中，氧化脱氨基作用比芳香羟基化作用更活跃。不同物种之间 AMP 代谢的总体速率存在显着差异；肝细胞悬浮液中的半衰期相差约 70 倍，兔小于大鼠，小于狗，小于松鼠猴 = 人。与其他物种相比，人类肝细胞对 AMP 的代谢在代谢物谱和速率方面与松鼠猴肝细胞的代谢非常相似。然而，苯丙酮（AMP 氧化脱氨的产物）在两种灵长类动物肝细胞中的分布情况有所不同。因此，分离的肝细胞对 AMP 的代谢对于所检查的每个物种来说都是独特的。这些研究证明了分离的肝细胞在研究肝脏异生物质代谢的种间差异方面的适用性，提供了一种易于适应人类肝脏组织的体外技术。
Isolated hepatocyte suspensions from rat, rabbit, dog, squirrel monkey and human livers were used to study the metabolism of amphetamine (AMP), a drug for which species-dependent differences in metabolism have been demonstrated in vivo. Hepatocytes were isolated by perfusion of the whole liver or of biopsy specimens. In general, the metabolite profile of hepatocytes from each species corresponded to the profile of urinary metabolites identified previously. Rat hepatocytes primarily metabolized AMP by aromatic hydroxylation to p-hydroxyamphetamine. Rabbit hepatocytes converted AMP almost exclusively to products of the oxidative deamination pathway. Metabolism by hepatocytes from the other three species was mixed, but oxidative deamination was somewhat more active than aromatic hydroxylation in dog, squirrel monkey and human hepatocytes. The overall rate of AMP metabolism differed significantly among the species; the half-life in the hepatocyte suspensions varied about 70-fold, with rabbit less than rat less than dog less than squirrel monkey = human. Metabolism of AMP by human hepatocytes mare closely resembled metabolism by squirrel monkey liver cells than the other species in terms of metabolite profile and rate. However, the disposition of phenylacetone, a product of oxidative deamination of AMP, varied in hepatocytes from the two primate species. Thus, the metabolism of AMP by isolated hepatocytes was unique for each species examined. These studies demonstrate the applicability of isolated hepatocytes to the study of interspecies differences in hepatic xenobiotic metabolism, providing an in vitro technique that can be readily adapted to human liver tissue.