Release of latent glucuronosyltransferase activity contributes to the sparing of glucuronidation in experimental liver injuries.
In patients with parenchymal liver disease, glucuronidation of drugs is generally preserved but oxidation is impaired. This study explores the effects of liver injuries induced in rats by the administration of acute carbon tetrachloride, chronic bile duct ligation and chronic choline deficiency for 30 weeks on the glucuronidation of p-nitrophenol and 1-naphthol, both before and after solubilization of the microsomes and compares this to three measures of oxidation. Cytochrome P450 content was reduced to 17% of control values after acute carbon tetrachloride and to 35% of control values after bile duct ligation. Cytochrome C reductase fell to 58 and 32% of control and aniline hydroxylase to 46 and 13%, respectively, after acute carbon tetrachloride and bile duct ligation. P-nitrophenol glucuronidation by native microsomes was 206 and 73% of controls in the respective models, while 1-naphthol glucuronidation was 167 and 66% of control. Latent uridine diphosphate-glucuronosyltransferase (UDP-GT) activity, that is, differences between solubilized and native activity, was decreased by each liver injury. Chronic choline deficiency had little effect on the oxidation and native glucuronidation activity, although latent glucuronidation activity was lower. These studies suggest a preservation of glucuronidation compared to oxidation at the microsomal level in these experimental liver injuries. The data also support the hypothesis that a release of latent UDP-GT activity may contribute to this phenomenon.
Desmond
P V
PV
Department of Gastroenterology, St Vincent's Hospital, Melbourne, Victoria, Australia.
Smyth
F E
FE
Mashford
M L
ML
D000818:Animals; D002252:Carbon Tetrachloride Poisoning / Q000378:metabolism*; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism*; D002796:Choline Deficiency / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005965:Glucuronates / Q000378:metabolism*; D014453:Glucuronosyltransferase / Q000378:metabolism*; D008105:Liver Cirrhosis, Biliary / Q000378:metabolism*; D008106:Liver Cirrhosis, Experimental / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D009284:Naphthols / Q000493:pharmacokinetics; D009596:Nitrophenols / Q000493:pharmacokinetics; D010084:Oxidation-Reduction; D051381:Rats; D017207:Rats, Sprague-Dawley
D005965:Glucuronates; D009284:Naphthols; D009596:Nitrophenols; C029350:1-naphthol; D003577:Cytochrome P-450 Enzyme System; D014453:Glucuronosyltransferase; C024836:4-nitrophenol