Biochemical basis for deficient paracetamol glucuronidation in cats: An interspecies comparison of enzyme constraint in liver microsomes
Biochemical basis for deficient paracetamol glucuronidation in cats: An interspecies comparison of enzyme constraint in liver microsomes
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DOI：
10.1111/j.2042-7158.1997.tb06822.x
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发表时间：
1997-04-01
影响因子：
3.3
通讯作者：
Greenblatt, DJ
中科院分区：
文献类型：
--
作者：
Court, MH;Greenblatt, DJ
与大多数其他哺乳动物物种不同，家猫对酚类化合物的葡醛酸化作用很差，因此对包括扑热息痛在内的许多药物的毒副作用非常敏感。在这项研究中，我们评估了限制所有尿苷5‘-二磷酸葡萄糖醛酸基转移酶(UGT)活性的特征-酶限制在这种药物代谢缺陷的病因学中的作用。去污剂激活实验使用来自猫(4)、狗(4)、人(4)和其他6个哺乳动物物种(各1个肝脏)的肝微粒体。此外，我们使用了来自Gunn大鼠的微生物体，这些微生物体对扑热息痛毒性敏感，因为遗传缺陷影响了所有家族1的UGT。在最佳洗涤剂浓度下，扑热息痛-UGT活性的增加被用作酶抑制的指标。与其他物种相比，猫科动物的天然活动(在没有洗涤剂的情况下测量)不到六分之一。然而，最佳洗涤剂处理倾向于增强而不是消除这种差异，这表明与其他物种相比，猫对扑热息痛-UGT的限制水平相对较低。同样，清洁剂处理未能缩小纯合突变大鼠和正常Gunn大鼠之间的天然活性差异。最初使用CHAPS((3-(3-cholamidopropyl)-dimethylammonio-1-propanesulphonic酸)作为洗涤剂激活剂；然而，在来自人类的4种微粒体制剂中，有3种在所有使用的洗涤剂浓度下都观察到抑制而不是激活。使用非离子洗涤剂Brij 58(聚氧乙烯20-十六烷基醚)重复研究，结果类似，但更深的激活和没有抑制。我们得出结论，猫的对乙酰氨基酚葡萄糖醛酸化缺陷不是由于与其他哺乳动物物种相比，对乙酰氨基酚UGT限制增加所致。其他原因，如酶蛋白浓度或底物亲和力的差异可能是原因之一。
Unlike most other mammalian species, domestic cats glucuronidate phenolic compounds poorly and are therefore highly susceptible to the toxic side effects of many drugs, including paracetamol. In this study, we evaluated the role of enzyme constraint, a characteristic that limits the activity of all uridine 5'-diphosphoglucuronosyltransferase (UGT) enzymes, in the aetiology of this species-dependent defect of drug metabolism.Detergent activation experiments were performed using hepatic microsomes from cats (4), dogs (4), man (4), and 6 other mammalian species (1 liver each). In addition, we used microsomes from Gunn rats which are sensitive to paracetamol toxicity because of a genetic defect affecting all family 1 UGTs. Increase in paracetamol-UGT activity at optimum concentrations of detergent was used as an index of enzyme constraint. Native activity (measured in the absence of detergent) was less than one-sixth in cats compared with other species. Optimum detergent treatment tended to enhance rather than abolish this difference, however, indicating relatively lower levels of constraint of paracetamol-UGT in cats compared with other species. Similarly, detergent treatment failed to reduce the native activity difference between homozygous mutant and normal Gunn rats. Initially CHAPS (3-(3-cholamidopropyl)-dimethylammonio-1-propanesulphonic acid) was used as the detergent activator; in 3 of 4 microsomal preparations from man, however, inhibition rather than activation was observed at all detergent concentrations used. Studies were repeated using the non-ionic detergent, Brij 58 (polyoxyethylene 20-cetyl ether), which resulted in similar although more profound activation and no inhibition.We conclude that deficient paracetamol glucuronidation in cats does not result from increased paracetamol UGT constraint in this species compared with other mammalian species. Other causes, such as differences in enzyme protein concentration or substrate affinity might be responsible.