Elsevier

Biochemical Pharmacology

Volume 36, Issue 18, 15 September 1987, Pages 2993-3000
Biochemical Pharmacology

Effects of adenosine on glucuronidation and uridine diphosphate glucuronic acid (UDPGA) synthesis in isolated rat hepatocytes

https://doi.org/10.1016/0006-2952(87)90214-0Get rights and content

Abstract

Dibutyryl cyclic adenosine 3':5'-monophosphate (DBcAMP) has been shown to inhibit glucuronidation of p-nitrophenol in a concentration-dependent manner in isolated rat hepatocytes. Adenosine (ADO) also decreased glucuronidation in a similar fashion. The effects of adenosine were examined on the variables controlling glucuronidation in intact cells. The addition of adenosine was without effect on either glucuronyltransferase or β-glucuronidase. Adenosine decreased undine diphosphate glucuronic acid (UDPGA) levels by 62% and, subsequently, inhibited glucuronidation by 41% in isolated rat hepatocytes. Since the synthesis of UDPGA requires NAD+ for the dehydrogenation of UDP-glucose, alterations in the redox state could account for the decrease in intracellular UDPGA levels. The effects of ADO (500 μM) on lactate and pyruvate content and redox state were examined in rat hepatocytes. ADO caused a 2.1-fold increase in lactate levels and a 2.65-fold increase in the [lactate]/ [pyruvate] ratio. The NAD+/NADP ratio, therefore, was decreased by 63% in the presence of ADO. Carbohydrate reserve also affects UDPGA levels; thus, graded concentrations of glucose (5.5, 25, and 50 mM) were added to cells incubated with ADO. At 5.5 mM glucose, ADO caused a 61% decrease in glucuronide formation, while at concentrations of 25 and 50 mM glucose, the inhibition was diminished by 53 and 47% respectively. ADO appears to have decreased the synthesis of UDPGA by decreasing the NAD+/NADH ratio, thus inhibiting UDP-glucose dehydrogenase. Carbohydrate reserve also appears to be involved in the inhibition of glucuronidation mediated by ADO.

References (63)

  • T.A. Miettinen et al.

    Biochem. Pharmac.

    (1963)
  • B. Muller-Oerlinghausen et al.

    Life Sci.

    (1967)
  • Y. Hinohara et al.

    Jap. J. Pharmacol.

    (1974)
  • J.H. Exton et al.

    Adv. Enzyme Regulat.

    (1968)
  • H. Selawry et al.

    Biochem. biophys. Res. Commun.

    (1973)
  • S.J. Pilkis et al.

    Biochim. biophys. Acta

    (1974)
  • L.S. Jefferson et al.

    J. biol. Chem.

    (1968)
  • A. Constantopoulos et al.

    Gastroenterology

    (1978)
  • L.A. Shipley et al.

    Biochem. Pharmac.

    (1985)
  • D. Ullrich et al.

    Biochem. Pharmac.

    (1984)
  • W. Lilienblum et al.

    Biochem. Pharmac.

    (1982)
  • B.M. Pogell et al.

    J. biol. Chem.

    (1961)
  • A. Winsnes

    Biochim. biophys. Acta

    (1972)
  • S.A. Belinsky et al.

    J. biol. Chem.

    (1984)
  • J.W. Phillis et al.

    Prog. Neurobiol.

    (1981)
  • T.W. Stone

    Neuroscience

    (1981)
  • G.J. Mulder et al.

    Biochem. Pharmac.

    (1974)
  • J. Singh et al.

    Biochem. Pharmac.

    (1981)
  • D. Ullrich et al.

    Biochem. Pharmac.

    (1984)
  • I.V. Deaciuc et al.

    Int. J. Biochem.

    (1981)
  • R.K. Studer et al.

    J. biol. Chem.

    (1982)
  • G.A. Rufo et al.

    Biochim. biophys. Acta

    (1981)
  • J. Wilkening et al.

    Biochim. biophys. Acta

    (1975)
  • V.Chagoya de Sanchez et al.

    Fedn Eur. Biochem. Soc. Lett.

    (1972)
  • P. Moldeus et al.

    Biochem. Pharmac.

    (1978)
  • A.R. Boobis et al.

    Biochem. Pharmac.

    (1974)
  • G.J. Dutton
  • G.J. Dutton et al.

    Prog. Drug Metab.

    (1977)
  • N.R. Moudgall et al.

    Endocrinology

    (1959)
  • G.J. Dutton
  • B. Muller-Oerlinghausen et al.

    Naunyn-Schmeideberg's Archs Pharmac. exp. Path.

    (1968)
  • Cited by (6)

    Present address: Walter Reed Army Institute of Research, Division of Experimental Therapeutics, Washington, DC 20307.

    View full text