Effect of volatile anesthetics on the hepatic UDP-glucuronic acid pathway in mice.
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.
Watkins
J B
JB
Pharmacology Section, Indiana University School of Medicine, Bloomington 47405.
Engles
D R
DR
Beck
L V
LV
D000777:Anesthetics / Q000494:pharmacology*; D000818:Animals; D004987:Ethers / Q000494:pharmacology; D005260:Female; D006221:Halothane / Q000494:pharmacology; D007530:Isoflurane / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008738:Methyl Ethers; D051379:Mice; D011755:Pyrophosphatases / Q000032:analysis; D000077149:Sevoflurane; D012737:Sex Factors; D014520:Urethane / Q000494:pharmacology; D014535:Uridine Diphosphate Glucuronic Acid / Q000032:analysis / Q000378:metabolism*; D014539:Uridine Diphosphate Sugars / Q000378:metabolism*
D000777:Anesthetics; D004987:Ethers; D008738:Methyl Ethers; D014539:Uridine Diphosphate Sugars; D014535:Uridine Diphosphate Glucuronic Acid; D000077149:Sevoflurane; D014520:Urethane; D007530:Isoflurane; D011755:Pyrophosphatases; C021899:nucleotide pyrophosphatase; D006221:Halothane