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Effect of volatile anesthetics on the hepatic UDP-glucuronic acid pathway in mice
J B Watkins1, D R Engles, L V Beck
1Pharmacology Section, Indiana University School of Medicine, Bloomington 47405.
Abstract:
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.
Insights
Inhalation anesthetics significantly reduce hepatic UDP-glucuronic acid (UDPGA) levels. Increased nucleotide pyrophosphatase activity in female mice contributes to this UDPGA depletion.
Area of Science:
- Biochemistry
- Pharmacology
- Toxicology
Background:
- Hepatic UDP-glucuronic acid (UDPGA) concentrations decrease rapidly after exposure to various chemicals, including inhalation anesthetics.
- This depletion can reach up to 80% within minutes, impacting drug metabolism and detoxification pathways.
Purpose of the Study:
- To investigate the mechanisms behind the anesthetic-induced decrease in hepatic UDPGA.
- To determine if changes in UDP-glucose precursor, UDP-glucose dehydrogenase, UDP-glucuronosyltransferase, or nucleotide pyrophosphatase activity are responsible.
Main Methods:
- Mice were exposed to halothane, isoflurane, and sevoflurane.
- Measurements included UDP-glucose levels, UDP-glucose dehydrogenase activity, UDP-glucuronosyltransferase activity, and nucleotide pyrophosphatase activity.
- Kinetic analysis of nucleotide pyrophosphatase was performed using 4-nitrophenol thymidine 5'-monophosphate ester.
Main Results:
- Anesthetics decreased UDPGA concentrations by 40-52% compared to controls.
- No significant sex-dependent or anesthetic-induced effects were observed on UDP-glucose levels or the activities of UDP-glucose dehydrogenase and UDP-glucuronosyltransferase.
- Nucleotide pyrophosphatase activity increased by 47-65% in female mice exposed to anesthetics.
- The Vmax for nucleotide pyrophosphatase hydrolysis increased significantly (56-80%) in female mice, while Km remained unchanged.
Conclusions:
- Increased nucleotide pyrophosphatase activity, particularly in female mice, plays a role in the anesthetic-induced depletion of hepatic UDPGA.
- Altered nucleotide pyrophosphatase kinetics contribute to the observed decrease in UDPGA concentrations during volatile anesthetic exposure.