Watkins J B, Engles D R, Beck L V
Pharmacology Section, Indiana University School of Medicine, Bloomington 47405.
Biochem Pharmacol. 1990 Aug 15;40(4):731-5. doi: 10.1016/0006-2952(90)90308-8.
Large, rapid decreases in hepatic UDP-glucuronic acid concentrations occur in rats following exposure to myriad chemicals. In fact, 80% reductions in UDP-glucuronic acid occur within minutes after exposure to inhalation anesthetics. The present study was designed to determine whether this decrease in hepatic UDP-glucuronic acid may be due to (a) a decrease in the precursor UDP-glucose; (b) decreased activity of UDP-glucose dehydrogenase, which oxidizes UDP-glucose to UDP-glucuronic acid; (c) increased activity of UDP-glucuronosyltransferases; or (d) increased activity of nucleotide pryophosphatase, which degrades UDP-glucuronic acid to glucuronic acid-1-phosphate. Exposure to halothane, isoflurane and sevoflurane decreased UDP-glucuronic acid concentrations by 40-52% as compared to that in unanesthetized control mice. No sex-dependent or anesthetic-induced effects of UDP-glucose levels and the activities of UDP-glucose dehydrogenase and UDP-glucuronosyltransferase were observed. Nucleotide pyrophosphatase activity was increased by 47-65% in female mice after inhalation of halothane, isoflurane and sevoflurane. The apparent Vmax for hydrolysis of 4-nitrophenol thymidine 5'-monophosphate ester by nucleotide pyrophosphatase was increased by 56-80% in female mice, whereas the apparent Km was unchanged. These alterations in nucleotide pyrophosphate kinetics may be responsible, in part, for the marked decrease of hepatic UDP-glucuronic acid concentrations by the volatile anesthetics.
大鼠接触多种化学物质后，肝脏中尿苷二磷酸葡萄糖醛酸（UDP - 葡萄糖醛酸）浓度会大幅迅速下降。事实上，吸入麻醉剂后几分钟内，UDP - 葡萄糖醛酸浓度就会降低80%。本研究旨在确定肝脏中UDP - 葡萄糖醛酸的这种降低是否可能是由于：（a）前体尿苷二磷酸葡萄糖（UDP - 葡萄糖）减少；（b）将UDP - 葡萄糖氧化为UDP - 葡萄糖醛酸的UDP - 葡萄糖脱氢酶活性降低；（c）UDP - 葡萄糖醛酸转移酶活性增加；或（d）将UDP - 葡萄糖醛酸降解为1 - 磷酸葡萄糖醛酸的核苷酸焦磷酸酶活性增加。与未麻醉的对照小鼠相比，接触氟烷、异氟烷和七氟烷后，UDP - 葡萄糖醛酸浓度降低了40 - 52%。未观察到UDP - 葡萄糖水平以及UDP - 葡萄糖脱氢酶和UDP - 葡萄糖醛酸转移酶的活性存在性别依赖性或麻醉诱导的影响。吸入氟烷、异氟烷和七氟烷后，雌性小鼠的核苷酸焦磷酸酶活性增加了47 - 65%。雌性小鼠中，核苷酸焦磷酸酶水解4 - 硝基苯酚胸苷5'-单磷酸酯的表观Vmax增加了56 - 80%，而表观Km不变。核苷酸焦磷酸动力学的这些改变可能部分导致了挥发性麻醉剂使肝脏UDP - 葡萄糖醛酸浓度显著降低。
