Abstract

The effect of adjuvant-induced arthritis on hepatic microsomal glucuronidation was studied in the rat. Arthritis was induced by injection of Mycobacterium butyricum suspended in liquid paraffin. V_max and the Michaelis-Menten constant values for the in vitro glucuronidation of R- andS-ketoprofen, acetaminophen, and diflunisal by liver microsomes obtained from control and adjuvant-induced arthritic rats were compared. In addition, uridine5′-diphosphate-glucuronosyltransferase activity toward bilirubin and p-nitrophenol, as well as levels of cytochrome P-450 and β-glucuronidase were determined in these microsomal preparations. Adjuvant-induced arthritis resulted in a significant reduction in hepatic cytochrome P-450 levels and inp-nitrophenol glucuronidation (5.65 ± 0.40 versus 2.58 ± 0.27 μmol·min/mg protein in control and arthritic rats, respectively, mean ± S.E.M.). Glucuronidation of bilirubin and β-glucuronidase activities in liver microsomes and in plasma were not affected by adjuvant-induced arthritis. V_max(nmol/min/mg protein) for the formation of R-ketoprofen glucuronide, S-ketoprofen glucuronide, diflunisal phenolic glucuronide, and diflunisal acyl glucuronide was significantly decreased in arthritic rats (0.68 ± 0.10, 0.77 ± 0.12, 0.044 ± 0.005, 0.26 ± 0.03, respectively) compared with control rats (1.45 ± 0.04, 1.60 ± 0.04, 0.087 ± 0.008, 0.46 ± 0.04, respectively). Glucuronidation ofp-nitrophenol, ketoprofen and diflunisal, substrates which seem to be at least partly glucuronidated in the rat by isoenzymes of the UGT2B subfamily, was impaired in adjuvant-induced arthritis. Glucuronidation of bilirubin and acetaminophen, substrates of UGT1- isoenzymes, was not affected by adjuvant-induced arthritis. It seems, therefore, that adjuvant-induced arthritis in the rat leads to impaired glucuronidation of substrates of the UGT2B subfamily.