Pathophysiological changes in human patients and in animal models of infection or inflammation are associated with alterations in the production of numerous liver-derived proteins including metabolizing enzymes. In this study, the effects of adjuvant-induced arthritis (AA) in rats on the levels of mRNA and activity of hepatic xenobiotic metabolizing enzymes were determined during the inflammatory response. The mRNA levels of cytochrome P450 (CYP) 1A2, CYP2C12, CYP2D1, CYP2D2, and CYP3A1 were significantly decreased compared with control levels in almost all phases of inflammation. A reduction in the activity of CYP2C and CYP3A, which are abundantly expressed in the liver, was also observed. For phase II metabolizing enzymes, mRNA levels of uridine 5’-diphospho-glucuronosyltransferase (UGT) 1A1, UGT1A6, sulfotransferase (SULT) 2A1, and glutathione S-transferase 2 were significantly decreased compared with control levels. However, the mRNA levels of UGT2B and SULT1A1 returned to control levels during the subacute (7 d after adjuvant treatment) and chronic (21 d after adjuvant treatment) phases although these levels decreased during the acute (3 d after adjuvant treatment) phase. These results suggest that the effects of inflammation on the expression of xenobiotic metabolizing enzymes differ depending on the isoform of the enzyme and could affect the pharmacokinetics of each substrate.
A. E. Aitken, T. A. Richardson and E. T. Morgan, “Regulation of Drug-Metabolizing Enzymes and Transporters in Inflammation,” Pharmacology and Toxicology, Vol. 46, 2006, pp. 123-149. doi:10.1146/annurev.pharmtox.46.120604.141059
K. W. Renton, “Cytochrome P450 Regulation and Drug Biotransformation during Inflammation and Infection,” Current Drug Metabolism, Vol. 5, No. 3, 2004, pp. 235-243. doi:10.2174/1389200043335559
F. M. Belpaire, F. D. Smet, B. F. Chidavijak, N. Fraeyman and M. G. Bogaert, “Effect of Turpentine-Induced Inflammation on the Disposition Kinetics of Propranolol, Metoprolol, and Antipyrine in the Rat,” Fundamental & Clinical Pharmacology, Vol. 3, No. 2, 1989, pp. 79-88. doi:10.1111/j.1472-8206.1989.tb00667.x
M. Piquette-Miller and F. Jamali, “Selective Effect of Adjuvant Arthritis on the Disposition of Propranolol Enantiomers in Rats Detected Using a Stereospecific HPLC Assay,” Pharmaceutical Research, Vol. 10, No. 2, 1993, pp. 294-299. doi:10.1023/A:1018907431893
M. E. Laethem, F. M. Belpaire, P. Wijnant, M. T. Rosseel and M. G. Bogaert, “Influence of Endotoxin on the Stereoselective Pharmacokinetics of Oxprenolol, Propranolol, and Verapamil in the Rat,” Chirality, Vol. 6, No. 5, 1994, pp. 405-410. doi:10.1002/chir.530060508
R. O. Williams, M. Feldmann and R. N. Maini, “AntiTumor Necrosis Factor Ameliorates Joint Disease in Murine Collagen-Induced Arthritis,” Proceedings of the National Academy of Sciences of the United States of America, Vol. 89, No. 20, 1992, pp. 9784-9788. doi:10.1073/pnas.89.20.9784
N. Shibata, H. Shimakawa, T. Minouchi and A. Yamaji, “Pharmacokinetics of Cyclosporin A after Intravenous Administration to Rats in Various Disease States,” Biological & Pharmaceutical Bulletin, Vol. 16, No. 11, 1993, pp. 1130-1135. doi:10.1248/bpb.16.1130
G. Dipasquale, P. Welaj and C. L. Rassaert, “Prolonged Pentobarbital Sleeping Time in Adjuvant-Induced Polyarthritic Rats,” Research Communications in Chemical Pathology and Pharmacology, Vol. 9, No. 2, 1974, pp. 253-264.
T. Nagao, T. Tanino and M. Iwaki, “Stereoselective Pharmacokinetics of Flurbiprofen and Formation of Covalent Adducts with Plasma Protein in Adjuvant-Induced Arthritic Rats,” Chirality, Vol. 15, No. 5, 2003, pp. 423-428. doi:10.1002/chir.10227
S. Uno, A. Kawase, A. Tsuji, T. Tanino and M. Iwaki, “Decreased Intestinal CYP3A and P-Glycoprotein Activities in Rats with Adjuvant Arthritis,” Drug Metabolism and Pharmacokinetics, Vol. 22, No. 4, 2007, pp. 313-321. doi:10.2133/dmpk.22.313
G. W. Warren, S. M. Poloyac, D. S. Gary, M. P. Mattson and R. A. Blouin, “Hepatic Cytochrome P-450 Expression in Tumor Necrosis Factor-Alpha Receptor (p55/p75) Knockout Mice after Endotoxin Administration,” Journal of Pharmacology and Experimental Therapeutics, Vol. 288, No. 3, 1999, pp. 945-950.
E. Siewert, R. Bort, R. Kluge, P. C. Heinrich, J. Castell and R. Jover, “Hepatic Cytochrome P450 Down-Regulation during Aseptic Inflammation in the Mouse Is Interleukin 6 Dependent,” Hepatology, Vol. 32, No. 1, 2000, pp. 49-55. doi:10.1053/jhep.2000.8532
E. T. Morgan, “Regulation of Cytochrome P450 by Inflammatory Mediators: Why and How?” Drug Metabolism and Disposition, Vol. 29, No. 3, 2001, pp. 207-212.
P. Honkakoski, I. Zelko, T. Sueyoshi and M. Negishi, “The Nuclear Orphan Receptor CAR-Retinoid X Receptor Heterodimer Activates the Phenobarbital-Responsive Enhancer Module of the CYP2B Gene,” Molecular and Cellular Biology, Vol. 18, No. 10, 1998, pp. 5652-5658.
S. A. Kliewer, J. T. Moore, L. Wade, J. L. Staudinger, M. A. Watson, S. A. Jones, D. D. McKee, B. B. Oliver, T. M. Willson, R. H. Zetterstrom, T. Perlmann and J. M. Lehmann, “An Orphan Nuclear Receptor Activated by Pregnanes Defines a Novel Steroid Signaling Pathway,” Cell, Vol. 92, No. 1, 1998, pp. 73-82. doi:10.1016/S0092-8674(00)80900-9
D. J. Waxman, “P450 Gene Induction by Structurally Diverse Xenochemicals: Central Role of Nuclear Receptors CAR, PXR, and PPAR,” Archives of Biochemistry and Biophysics, Vol. 369, No. 1, 1999, pp. 11-23. doi:10.1006/abbi.1999.1351
A. Kawase, A. Fujii, M. Negoro, R. Akai, M. Ishikubo, H. Komura and M. Iwaki, “Differences in Cytochrome P450 and Nuclear Receptor mRNA Levels in Liver and Small Intestine between SD and DA Rats,” Drug Metabolism and Pharmacokinetics, Vol. 23, No. 3, 2008, pp. 196-206. doi:10.2133/dmpk.23.196
H. Sanada, M. Sekimoto, A. Kamoshita and M. Degawa, “Changes in Expression of Hepatic Cytochrome P450 Subfamily Enzymes during Development of AdjuvantInduced Arthritis in Rats,” Journal of Toxicological Sciences, Vol. 36, No. 2, 2011, pp. 181-190. doi:10.2131/jts.36.181
E. Assenat, S. Gerbal-Chaloin, D. Larrey, J. Saric, J. M. Fabre, P. Maurel, M. J. Vilarem and J. M. Pascussi, “Interleukin 1β Inhibits CAR-Induced Expression of Hepatic Genes Involved in Drug and Bilirubin Clearance,” Hepatology, Vol. 40, No. 4, 2009, pp. 951-960.
S. A. Kliewer, J. T. Moore, L. Wade, J. L. Staudinger, M. A. Watson, S. A. Jones, D. D. McKee, B. B. Oliver, T. M. Willson, R. H. Zetterstrom, T. Perlmann and J. M. Lehmann, “An Orphan Nuclear Receptor Activated by Pregnanes Defines a Novel Steroid Signaling Pathway,” Cell, Vol. 92, No. 1, 1998, pp. 73-82. doi:10.1016/S0092-8674(00)80900-9
B. Goodwin, E. Hodgson and C. Liddle, “The Orphan Human Pregnane X Receptor Mediates the Transcriptional Activation of CYP3A4 by Rifampicin through a Distal Enhancer Module,” Molecular Pharmacology, Vol. 56, No. 6, 1999, pp. 1329-1339.
J. M. Maglich, C. M. Stoltz, B. Goodwin, D. HawkinsBrown, J. T. Moore and S. A. Kliewer, “Nuclear Pregnane x Receptor and Constitutive Androstane Receptor Regulate Overlapping but Distinct Sets of Genes Involved in Xenobiotic Detoxification,” Molecular Pharmacology, Vol. 62, No. 3, 2002, pp. 638-646. doi:10.1124/mol.62.3.638
T. Izukawa, M. Nakajima, R. Fujiwara, H. Yamanaka, T. Fukami, M. Takamiya, Y. Aoki, S. Ikushiro, T. Sakaki and T. Yokoi, “Quantitative Analysis of UDP-Glucuronosyltransferase (UGT) 1A and UGT2B Expression Levels in Human Livers,” Drug Metabolism and Disposition, Vol. 37, No. 8, 2009, pp. 1759-1768. doi:10.1124/dmd.109.027227
R. L. Yeager, S. A. Reisman, L. M. Aleksunes and C. D. Klaassen, “Introducing the TCDD-Inducible AhR-Nrf2 Gene Battery,” Toxicological Sciences, Vol. 111, No. 2, 2009, pp. 238-246. doi:10.1093/toxsci/kfp115
S. Chen, D. Beaton, N. Nguyen, K. Seneko-Effenberger, E. Brace-Sinnokrak, U. Argikar, R. P. Remmel, J. Trottier, O. Barbier, J. K. Ritter and R. H. Tukey, “Tissue-Specific, Inducible, and Hormonal Control of the Human UDP-Glucuronosyltransferase-1 (UGT1) Locus,” Journal of Biological Chemistry., Vol. 280, 2005, pp. 37547-37557. doi:10.1074/jbc.M506683200
T. P. Dooley, R. Haldeman-Cahill, J. Joiner and T. W. Wilborn, “Expression Profiling of Human Sulfotransferase and Sulfatase Gene Superfamilies in Epithelial Tissues and Cultured Cells,” Biochemical and Biophysical Research Communications, Vol. 277, No. 1, 2000, pp. 236-245. doi:10.1006/bbrc.2000.3643
M. Runge-Morris, W. Wu and T. A. Kocarek, “Regulation of Rat Hepatic Hydroxysteroid Sulfotransferase (SULT2-40/41) Gene Expression by Glucocorticoids: Evidence for a Dual Mechanism of Transcriptional Control,” Molecular Pharmacology, Vol. 56, No. 6, 1999, pp. 1198-1206.
J. Sonoda, W. Xie, J. M. Rosenfeld, J. L. Barwick, P. S. Guzelian and R. M. Evans, “Regulation of a Xenobiotic Sulfonation Cascade by Nuclear Pregnane X Receptor (PXR),” Proceedings of the National Academy of Sciences of the United States of America, Vol. 99, No. 21, 2002, pp. 13801-13806. doi:10.1073/pnas.212494599
S. Uno, M. Uraki, A. Ito, Y. Shinozaki, A. Yamada, A. Kawase and M. Iwaki, “Changes in mRNA Expression of ABC and SLC Transporters in Liver and Intestines of the Adjuvant-Induced Arthritis Rat,” Biopharmaceutics & Drug Disposition, Vol. 30, No. 1, 2009, pp. 49-54. doi:10.1002/bdd.639