Effects of adenosine on glucuronidation and uridine diphosphate glucuronic acid (UDPGA) synthesis in isolated rat hepatocytes.
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 beta-glucuronidase. Adenosine decreased uridine 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 microM) 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.
Shipley
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Weiner
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D000227:Adenine Nucleotides / Q000378:metabolism; D000241:Adenosine / Q000494:pharmacology*; D000818:Animals; D003994:Bucladesine / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D005215:Fasting; D005947:Glucose / Q000378:metabolism; D005965:Glucuronates / Q000378:metabolism*; D006003:Glycogen / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D014535:Uridine Diphosphate Glucuronic Acid / Q000096:biosynthesis*; D014539:Uridine Diphosphate Sugars / Q000096:biosynthesis*
D000227:Adenine Nucleotides; D005965:Glucuronates; D014539:Uridine Diphosphate Sugars; D014535:Uridine Diphosphate Glucuronic Acid; D003994:Bucladesine; D006003:Glycogen; D000242:Cyclic AMP; D005947:Glucose; D000241:Adenosine