Glucuronidation of R- and S-ketoprofen, acetaminophen, and diflunisal by liver microsomes of adjuvant-induced arthritic rats

The effect of adjuvant-induced arthritis on hepatic microsomal glucuronidat ion was studied in the rat. Arthritis was induced by injection of Mycobacte rium butyricum suspended in liquid paraffin. V-max and the Michaelis-Menten constant values for the in vitro glucuronidation of R- and S-ketoprofen, a cetaminophen, and diflunisal by liver microscmes obtained from control and adjuvant-induced arthritic rats were compared. In addition, uridine 5'-diph osphate-glucuronosyltransferase activity toward bilirubin and p-nitrophenol , as well as levels of cytochrome P-450 and beta-glucuronidase were determi ned in these microsomal preparations. Adjuvant-induced arthritis resulted i n a significant reduction in hepatic cytochrome P-450 levels and in p-nitro phenol glucuronidation (5.65 +/- 0.40 versus 2.58 +/- 0.27 mu mol-min/mg pr otein in control and arthritic rats, respectively, mean +/- S.E.M.). Glucur onidation of bilirubin and P-glucuronidase activities in liver microsomes a nd in plasma were not affected by adjuvant-induced arthritis. V-max (nmol/m in/mg protein) for the formation of R-ketoprofen glucuronide, S-ketoprofen glucuronide, diflunisal phenolic glucuronide, and diflunisal acyl glucuroni de 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 ra ts (1.45 +/- 0,04, 1.60 +/- 0.04, 0.087 +/- 0.008, 0.46 +/- 0.04, respectiv ely). Glucuronidation of p-nitrophenol, ketoprofen and diflunisal, substrat es which seem to be at least partly glucuronidated in the rat by isoenzymes of the UGT2B subfamily, was impaired in adjuvant-induced arthritis. Glucur onidation of bilirubin and acetaminophen, substrates of UGT1- isoenzymes, w as not affected by adjuvant-induced arthritis. It seems, therefore, that ad juvant-induced arthritis in the rat leads to impaired glucuronidation of su bstrates of the UGT2B subfamily.