Molecular basis for deficient acetaminophen glucuronidation in cats
Molecular basis for deficient acetaminophen glucuronidation in cats
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DOI：
10.1016/s0006-2952(97)00072-5
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发表时间：
1997-04-04
影响因子：
5.8
通讯作者：
Grenblatt, DJ
中科院分区：
文献类型：
--
作者：
Court, MH;Grenblatt, DJ
猫对对乙酰氨基酚毒性高度敏感，因为该药物在体内葡萄糖醛酸化不足。这种缺陷的酶动力学基础是未知的。因此，研究了对乙酰氨基酚UDP-葡萄糖醛酸基转移酶（对乙酰氨基酚-UGT）的动力学特性，使用猫肝微粒体（N = 4）与对对乙酰氨基酚中毒不太敏感的物种（包括犬（N = 4）、人（N = 4）和其他6种哺乳动物物种（各1个肝脏））的肝微粒体进行比较。还研究了古恩大鼠，因为它们表达有缺陷的UGT家族1同工酶，并且也倾向于对乙酰氨基酚毒性。对乙酰氨基酚动力学在所有情况下都是双相的，具有不同的高和低亲和力组分。猫微粒体中高亲和力活性的Km值（0.31 +/- 0.1 mM;平均值+/- SEM）介于犬（0.11 +/- 0.02 mM）和人（0.60 +/- 0.06 mM）以及其他种属（0.22 - 6.7 mM;范围）之间。另一方面，猫微粒体中的高亲和力Vmax值（0.025 +/- 0.006 nmol/min/mg）比犬（0.92 +/- 0.09 nmol/min/mg）和人（0.27 +/- 0.09 nmol/min/mg）低10倍以上;比其他种属的微粒体低5倍以上（范围为0.13 - 7.63 nmol/min/mg）。古恩大鼠微粒体显示，在纯合突变体（0.67 nmol/min/mg）和纯合正常（6.75 nmol/min/mg）动物之间，高亲和力V-max值存在相似的10倍差异。这些结果表明，相对于许多其他物种，猫具有显著低的高亲和力对乙酰氨基酚-UGT的肝脏水平。这种差异足以解释对乙酰氨基酚体内葡萄糖醛酸化不良和对乙酰氨基酚中毒的易感性。(C)1997年爱思唯尔科学公司
Cats are highly susceptible to acetaminophen toxicity because of deficient glucuronidation of this drug in vivo. The enzyme kinetic basis for this defect is unknown. Therefore, the kinetic properties of acetaminophen UDP-glucuronosyltransferase (acetaminophen-UGT) were investigated, using hepatic microsomes from cats (N = 4) compared with those of species that are less sensitive to acetaminophen intoxication including dogs (N = 4), humans (N = 4), and six other mammalian species (one liver from each). Gunn rats were also studied, since they express defective UGT family 1 isoenzymes and are also prone to acetaminophen toxicity. Acetaminophen kinetics were biphasic in all instances with distinct high and low affinity components. K-m values for the high affinity activity in cat microsomes (0.31 +/- 0.1 mM; mean +/- SEM) were intermediate between those of dogs (0.11 +/- 0.02 mM) and humans (0.60 +/- 0.06 mM) and other species (0.22 to 6.7 mM; range). On the other hand, high affinity V-max values were over 10-fold less in cat microsomes (0.025 +/- 0.006 nmol/min/mg) than in dogs (0.92 +/- 0.09 nmol/min/mg) and humans (0.27 +/- 0.09 nmol/min/mg); and over 5-fold less compared with microsomes from other species (range 0.13 to 7.63 nmol/min/mg). Gunn rat microsomes showed a similar 10-fold difference in high affinity V-max values between the homozygous mutant (0.67 nmol/min/mg) and homozygous normal (6.75 nmol/min/mg) animals. These results demonstrate that, relative to a number of other species, cats have remarkably low hepatic levels of a high affinity acetaminophen-UGT. This difference is sufficient enough to explain poor glucuronidation of acetaminophen in vivo and susceptibility to acetaminophen intoxication. (C) 1997 Elsevier Science Inc.