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. 1984 May 1;219(3):707–712. doi: 10.1042/bj2190707

Control of glucuronidation during hypoxia. Limitation by UDP-glucose pyrophosphorylase.

T Y Aw, D P Jones
PMCID: PMC1153535  PMID: 6331395

Abstract

The regulation of glucuronidation during hypoxia was studied in isolated hepatocytes by analysing the dependence of acetaminophen glucuronidation rate on the intracellular concentrations of UTP, glucose 1-phosphate, UDP-glucose and UDP-glucuronic acid. The steady-state concentrations of these metabolites in cells from fed and starved rats were altered by exposure to various hypoxic O2 concentrations and by adding exogenous glucose. Changes in glucuronidation rate under all conditions were explained in terms of the concentrations of the substrates for UDP-glucose pyrophosphorylase, i.e. UTP and glucose 1-phosphate. Steady-state rates for the UDP-glucose pyrophosphorylase reaction, calculated by using published kinetic constants and measured glucose 1-phosphate and UTP concentrations, were in agreement with the measured glucuronidation rates. Thus the UDP-glucose pyrophosphorylase reaction is the key regulatory site for drug glucuronidation during hypoxia. Control at this site indicates that glucuronidation in vivo may be generally depressed in pathological conditions involving hypoxia and energy (calorie) malnutrition.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Albrecht G. J., Bass S. T., Seifert L. L., Hansen R. G. Crystallization and properties of uridine diphosphate glucose pyrophosphorylase from liver. J Biol Chem. 1966 Jun 25;241(12):2968–2975. [PubMed] [Google Scholar]
  2. Aw T. Y., Jones D. P. Direct determination of UDP-glucuronic acid in cell extracts by high-performance liquid chromatography. Anal Biochem. 1982 Nov 15;127(1):32–36. doi: 10.1016/0003-2697(82)90140-3. [DOI] [PubMed] [Google Scholar]
  3. Aw T. Y., Jones D. P. Intracellular inhibition of UDP-glucose dehydrogenase during ethanol oxidation. Chem Biol Interact. 1983 Mar;43(3):283–288. doi: 10.1016/0009-2797(83)90112-6. [DOI] [PubMed] [Google Scholar]
  4. Aw T. Y., Jones D. P. Secondary bioenergetic hypoxia. Inhibition of sulfation and glucuronidation reactions in isolated hepatocytes at low O2 concentration. J Biol Chem. 1982 Aug 10;257(15):8997–9004. [PubMed] [Google Scholar]
  5. Bock K. W., Fröhling W., Remmer H., Rexer B. Effects of phenobarbital and 3-methylcholanthrene on substrate specificity of rat liver microsomal UDP-glucuronyltransferase. Biochim Biophys Acta. 1973 Nov 15;327(1):46–56. doi: 10.1016/0005-2744(73)90102-2. [DOI] [PubMed] [Google Scholar]
  6. Hess D. S., Bache R. J. Transmural distribution of myocardial blood flow during systole in the awake dog. Circ Res. 1976 Jan;38(1):5–15. doi: 10.1161/01.res.38.1.5. [DOI] [PubMed] [Google Scholar]
  7. Jones D. P. Determination of pyridine dinucleotides in cell extracts by high-performance liquid chromatography. J Chromatogr. 1981 Oct 9;225(2):446–449. doi: 10.1016/s0378-4347(00)80293-5. [DOI] [PubMed] [Google Scholar]
  8. Jones D. P., Mason H. S. Gradients of O2 concentration in hepatocytes. J Biol Chem. 1978 Jul 25;253(14):4874–4880. [PubMed] [Google Scholar]
  9. Moldéus P., Andersson B., Gergely V. Regulation of glucuronidation and sulfate conjugation in isolated hepatocytes. Drug Metab Dispos. 1979 Nov-Dec;7(6):416–419. [PubMed] [Google Scholar]
  10. Moldéus P., Andersson B., Norling A. Interaction of ethanol oxidation with glucuronidation in isolated hepatocytes. Biochem Pharmacol. 1978;27(22):2583–2588. doi: 10.1016/0006-2952(78)90331-3. [DOI] [PubMed] [Google Scholar]
  11. Moldéus P., Högberg J., Orrenius S. Isolation and use of liver cells. Methods Enzymol. 1978;52:60–71. doi: 10.1016/s0076-6879(78)52006-5. [DOI] [PubMed] [Google Scholar]
  12. OLIVER I. T. Inhibitor studies on uridine diphosphoglucose pyrophosphorylase. Biochim Biophys Acta. 1961 Sep 2;52:75–81. doi: 10.1016/0006-3002(61)90905-2. [DOI] [PubMed] [Google Scholar]
  13. Sadurska B., Szymczyk T. Properties of UDPG pyrophosphorylase from rat salivary glands and liver. Arch Oral Biol. 1978;23(8):639–646. doi: 10.1016/0003-9969(78)90188-7. [DOI] [PubMed] [Google Scholar]
  14. Singh J., Schwarz L. R. Dependence of glucuronidation rate on UDP-glucuronic acid levels in isolated hepatocytes. Biochem Pharmacol. 1981 Dec 1;30(23):3252–3254. doi: 10.1016/0006-2952(81)90528-1. [DOI] [PubMed] [Google Scholar]
  15. Thurman R. G., Reinke L. A., Belinsky S., Evans R. K., Kauffman F. C. Co-regulation of the mixed-function oxidation of p-nitroanisole and glucuronidation of p-nitrophenol in the perfused rat liver by carbohydrate reserves. Arch Biochem Biophys. 1981 Jun;209(1):137–142. doi: 10.1016/0003-9861(81)90265-4. [DOI] [PubMed] [Google Scholar]
  16. Winsnes A. Kinetic properties of different forms of hepatic UDPglucuronyltransferase. Biochim Biophys Acta. 1972 Oct 12;284(2):394–405. doi: 10.1016/0005-2744(72)90135-0. [DOI] [PubMed] [Google Scholar]

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