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. Vmax 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. Vmax(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.
Footnotes
-
Send reprint requests to: Dr. Roger K. Verbeeck, UCL/FATC 7355, School of Pharmacy, Av. E. Mounier 73, 1200 Brussels, Belgium email: verbeeck{at}fatc.ucl.ac.be
- Abbreviations used are::
- CYP-450
- cytochrome P450
- UDP
- uridine 5′-diphosphate
- UGT
- UDP-glucuronosyltransferase
- UDPGA
- UDP-glucuronic acid
- HPLC
- high-performance liquid chromatography
- AG
- acetaminophen glucuronide
- R-KG
- R-ketoprofen glucuronide
- S-KG
- S-ketoprofen glucuronide
- DPG
- diflunisal phenolic glucuronide
- DAG
- diflunisal acyl glucuronide
- UGT-pnp
- UGT activity toward p-nitrophenol
- Received April 15, 1998.
- Accepted July 15, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
DMD articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|