Glycogenolysis--and not gluconeogenesis--is the source of UDP-glucuronic acid for glucuronidation.
Differences in cofactor (NADPH and UDP-glucuronic acid) supply for various processes of biotransformation were studied by investigating the interrelations between glucose production (gluconeogenesis and glycogenolysis) and drug (p-nitrophenol, aminopyrine, phenolphthalein) biotransformation (hydroxylation and conjugation) in isolated murine hepatocytes. In glycogen-depleted hepatocytes prepared from animals fasted for 48 h (i) p-nitrophenol conjugation was decreased by 80% compared to the fed control, while aminopyrine oxidation was unaltered, (ii) addition of glucose or gluconeogenic substrates failed to increase the rate of p-nitrophenol conjugation, while the rate of p-nitrophenol and also aminopyrine oxidation was increased and (iii) gluconeogenesis was inhibited by 80% by aminopyrine oxidation: it was moderately decreased by p-nitrophenol oxidation and conjugation and remained unchanged by phenolphthalein conjugation. In hepatocytes prepared from fed mice (i) p-nitrophenol conjugation was independent of the extracellular glucose concentration, (ii) it was linked to the consumption of glycogen--addition of fructose inhibited p-nitrophenol glucuronidation only, while sulfation was unaltered and (iii) p-nitrophenol oxidation was not detectable: aminopyrine oxidation was not affected by fructose addition. It is suggested that UDP-glucuronic acid for glucuronidation derives predominantly from glycogen, while the NADPH generation for mixed function oxidation is linked to glucose uptake and/or gluconeogenesis in the liver.
Bánhegyi
G
G
1st Institute of Biochemistry, Semmelweis University, Medical School, Budapest, Hungary.
Garzó
T
T
Antoni
F
F
Mandl
J
J
D000632:Aminopyrine / Q000494:pharmacology; D000818:Animals; D001711:Biotransformation; D005215:Fasting; D005943:Gluconeogenesis; D005965:Glucuronates / Q000378:metabolism; D066298:In Vitro Techniques; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008112:Liver Glycogen / Q000378:metabolism*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009596:Nitrophenols / Q000494:pharmacology; D020113:Phenolphthalein; D010635:Phenolphthaleins / Q000494:pharmacology; D014535:Uridine Diphosphate Glucuronic Acid / Q000378:metabolism*; D014539:Uridine Diphosphate Sugars / Q000378:metabolism*
D005965:Glucuronates; D008112:Liver Glycogen; D009596:Nitrophenols; D010635:Phenolphthaleins; D014539:Uridine Diphosphate Sugars; D000632:Aminopyrine; D014535:Uridine Diphosphate Glucuronic Acid; D020113:Phenolphthalein; C024836:4-nitrophenol