Metabolic activation of diclofenac by human cytochrome P450 3A4: Role of 5-hydroxydiclofenac

Chemical Research in Toxicology

Volumn 12, Issue 2, 1999, Pages 214-222

  Shen, Sijiu ^a,d   Marchick, Michael R ^a   Davis, Margaret R ^b   Doss, George A ^b   Pohl, Lance R ^a,c  

^a NATIONAL INSTITUTES OF HEALTH   (United States)

^b MERCK RESEARCH LABORATORIES   (United States)

^c NATIONAL HEART LUNG AND BLOOD INSTITUTE   (United States)

^d PENN STATE COLLEGE OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

5 HYDROXYDICLOFENAC; CYTOCHROME P450 2C9; CYTOCHROME P450 3A4; CYTOCHROME P450 ISOENZYME; DICLOFENAC; EDETIC ACID; GLUTATHIONE; REDUCED NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE; TROLEANDOMYCIN; UNCLASSIFIED DRUG;

ANIMAL CELL; ARTICLE; CATALYSIS; CONTROLLED STUDY; DRUG ACTIVATION; DRUG OXIDATION; ENZYME ACTIVATION; HUMAN; HUMAN CELL; LIVER MICROSOME METABOLISM; LIVER TOXICITY; MALE; NONHUMAN; RAT;

ANIMALS; ANTI-INFLAMMATORY AGENTS, NON-STEROIDAL; ARYL HYDROCARBON HYDROXYLASES; CYTOCHROME P-450 ENZYME SYSTEM; DICLOFENAC; GAS CHROMATOGRAPHY-MASS SPECTROMETRY; HUMANS; MALE; MICROSOMES, LIVER; MIXED FUNCTION OXYGENASES; RATS; RATS, SPRAGUE-DAWLEY; STEROID 16-ALPHA-HYDROXYLASE; STEROID HYDROXYLASES;

ANIMALIA; UNIDENTIFIED BACULOVIRUS;

EID: 0033048697     PISSN: 0893228X     EISSN: None     Source Type: Journal    
DOI: 10.1021/tx9802365     Document Type: Article

References (52)

1. Small, R. E. (1989) Diclofenac sodium. Clin. Pharm. 8, 545-558.
2. Ouellette, G. S., Slitzky, B. E., Gates, J. A., Lagarde, S., and West, A. B. (1991) Reversible hepatitis associated with diclofenac. J. Clin. Gastroenterol. 13, 205-210.
3. Banks, A. T., Zimmerman, H. J., Ishak, K. G., and Harter, J. G. (1995) Diclofenac-associated hepatotoxicity: analysis of 180 cases reported to the Food and Drug Administration as adverse reactions. Hepatology 22, 820-827.
4. Breen, E. G., McNicholl, J., Cosgrove, E., McCabe, J., and Stevens, F. M. (1986) Fatal hepatitis associated with diclofenac. Gut 27, 1390-1393.
5. Schapira, D., Bassan, L., Nahir, A. M., and Scharf, Y. (1986) Diclofenac-induced hepatotoxicity. Postgrad. Med. J. 62, 63-65.
6. Sallie, R. W., McKenzie, T., Reed, W. D., Quinlan, M. F., and Shilkin, K. B. (1991) Diclofenac hepatitis. Aust. N. Z. J. Med. 21, 251-255.
7. Ohana, M., Hajiro, K., Takakuwa, H., and Okazaki, K. (1997) Recovery from diclofenac-induced hypersensitive fulminant hepatitis and prostaglandins [letter]. Dig. Dis. Sci. 42, 2031-2032.
8. Dunk, A. A., Walt, R. P., Jenkins, W. J., and Sherlock, S. S. (1982) Diclofenac hepatitis. Br. Med. J. (Clin. Res. Ed.) 284, 1605-1606.
9. Helfgott, S. M., Sandberg-Cook, J., Zakim, D., and Nestler, J. (1990) Diclofenac-associated hepatotoxicity. JAMA, J. Am. Med. Assoc. 264, 2660-2662.
10. Iveson, T. J., Ryley, N. G., Kelly, P. M., Trowell, J. M., McGee, J. O., and Chapman, R. W. (1990) Diclofenac associated hepatitis. J. Hepatol. 10, 85-89.
11. Purcell, P., Henry, D., and Melville, G. (1991) Diclofenac hepatitis. Gut 32, 1381-1385.
12. Boelsterli, U. A., Zimmerman, H. J., and Kretz-Rommel, A. (1995) Idiosyncratic liver toxicity of nonsteroidal antiinflammatory drugs: molecular mechanisms and pathology. Crit. Rev. Toxicol. 25, 207-235.
13. Pumford, N. R., Myers, T. G., Davila, J. C., Highet, R. J., and Pohl, L. R. (1993) Immunochemical detection of liver protein adducts of the nonsteroidal anti-inflammatory drug diclofenac. Chem. Res. Toxicol. 6, 147-150.
14. Hargus, S. J., Amouzedeh, H. R., Pumford, N. R., Myers, T. G., McCoy, S. C., and Pohl, L. R. (1994) Metabolic activation and immunochemical localization of liver protein adducts of the nonsteroidal anti-inflammatory drug diclofenac. Chem. Res. Toxicol. 7, 575-582.
15. Kretz-Rommel, A., and Boelsterli, U. A. (1994) Selective protein adducts to membrane-proteins in cultured rat hepatocytes exposed to diclofenac: radiochemical and immunochemical analysis. Mol. Pharmacol. 45, 237-244.
16. Gil, M. L., Ramirez, M. C., Terencio, M. C., and Castell, J. V. (1995) Immunochemical detection of protein adducts in cultured human hepatocytes exposed to diclofenac. Biochim. Biophys. Acta 1272, 140-146.
17. Wade, L. T., Kenna, J. G., and Caldwell, J. (1997) Immunochemical identification of mouse hepatic protein adducts derived from the nonsteroidal anti-inflammatory drugs diclofenac, sulindac, and ibuprofen. Chem. Res. Toxicol. 10, 546-555.
18. Seitz, S., Kretz-Rommel, A., Oude, E. R., and Boelsterli, U. A. (1998) Selective protein adduct formation of diclofenac glucuronide is critically dependent on the rat canalicular conjugate export pump (Mrp2). Chem. Res. Toxicol. 11, 513-519.
19. Kretz-Rommel, A., and Boelsterli, U. A. (1993) Diclofenac covalent protein-binding is dependent on acyl glucuronide formation and is inversely related to P450-mediated acute cell injury in cultured rat hepatocytes. Toxicol. Appl. Pharmacol. 120, 155-161.
20. Kretz-Rommel, A., and Boelsterli, U. A. (1994) Mechanism of covalent adduct formation of diclofenac to rat hepatic-microsomal proteins: retention of the glucuronic-acid moiety in the adduct. Drug Metab. Dispos. 22, 956-961.
21. Hargus, S. J., Martin, B. M., George, J. W., and Pohl, L. R. (1995) Covalent modification of rat liver dipeptidyl peptidase IV (CD26) by the nonsteroidal anti-inflammatory drug diclofenac. Chem. Res. Toxicol. 8, 993-996.
22. Kretz-Rommel, A., and Boelsterli, U. A. (1995) Cytotoxic activity of T cells and non-T cells from diclofenac-immunized mice against cultured syngeneic hepatocytes exposed to diclofenac. Hepatology 22, 213-222.
23. Shen, S., Hargus, S. J., Martin, B. M., and Pohl, L. R. (1997) Cytochrome P4502C11 is a target of diclofenac covalent binding in rats. Chem. Res. Toxicol. 10, 420-423.
24. Homberg, J. C., Andre, C., and Abuaf, N. (1984) A new anti-liver-kidney microsome antibody (anti-LKM2) in tienilic acid-induced hepatitis. Clin. Exp. Immunol. 55, 561-570.
25. Beaune, Ph., Dansette, P. M., Mansuy, D., Kiffel, L., Finck, M., Amar, C., Leroux, J. P., and Homberg, J. C. (1987) Human anti-endoplasmic reticulum autoantibodies appearing in a drug-induced hepatitis are directed against a human liver cytochrome P-450 that hydroxylates the drug. Proc. Natl. Acad. Sci. U.S.A. 84, 551-555.
26. Neuberger, J., and Williams, R. (1989) Immune mechanisms in tienilic acid associated hepatotoxicity. Gut 30, 515-519.
27. Robin, M. A., Maratrat, M., LeRoy, M., LeBreton, F. P., Bonierbale, E., Dansette, P., Ballet, F., Mansuy, D., and Pessayre, D. (1996) Antigenic targets in tienilic acid hepatitis: Both cytochrome P450 2C11 and 2C11-tienilic acid adducts are transported to the plasma membrane of rat hepatocytes and recognized by human sera. J. Clin. Invest. 98, 1471-1480.
28. Yasumori, T., Kawano, S., Nagata, K., Shimada, M., Yamazoe, Y., and Kato, R. (1987) Nucleotide-sequence of a human-liver cytochrome-P-450 related to the rat male specific form. J. Biochem. 102, 1075-1082.
29. Lecoeur, S., Bonierbale, E., Challine, D., Gautier, J. C., Valadon, P., Dansette, P. M., Catinot, R., Ballet, F., Mansuy, D., and Beaune, P. H. (1994) Specificity of in-vitro covalent binding of tienilic acid metabolites to human liver-microsomes in relationship to the type of hepatotoxicity: comparison with 2 directly hepatotoxic drugs. Chem. Res. Toxicol. 7, 434-442.
30. Leemann, T., Transon, C., and Dayer, P. (1993) Cytochrome-P450TB (CYP2C): a major monooxygenase catalyzing diclofenac 4′-hydroxylation in human liver. Life Sci. 52, 29-34.
31. Yamazaki, H., Inoue, K., Chiba, K., Ozawa, N., Kawai, T., Suzuki, Y., Goldstein, J. A., Guengerich, F. P., and Shimada, T. (1998) Comparative studies on the catalytic roles of cytochrome P450 2C9 and its Cys- and Leu-variants in the oxidation of Warfarin, flurbiprofen, and diclofenac by human liver microsomes. Biochem. Pharmacol. 56, 243-251.
32. Omura, T., and Sato, R. (1964) The carbon monoxide-binding pigment of liver microsomes. J. Biol. Chem. 239, 2379-2385.
33. Harris, J. W., Rahman, A., Kim, B. R., Guengerich, F. P., and Collins, J. M. (1994) Metabolism of taxol by human hepatic microsomes and liver slices: participation of cytochrome-P450 3A4 and an unknown P450 enzyme. Cancer Res. 54, 4026-4035.
34. Stierlin, H., Faigle, J. W., Sallmann, A., Küng, W., Richter, W. J., Kriemler, H. P., Alt, K. O., and Winkler, T. (1979) Biotransformation of diclofenac sodium (Voltaren) in animals and in man. I. Isolation and identification of principal metabolites. Xenobiotica 9, 601-610.
35. Wrighton, S. A., Vandenbranden, M., Stevens, J. C., Shipley, L. A., Ring, B. J., Rettie, A. E., and Cashman, J. R. (1993) In-vitro methods for assessing human hepatic drug-metabolism: their use in drug development. Drug Metab. Rev. 25, 453-484.
36. Ono, S., Hatanaka, T., Hotta, H., Satoh, T., Gonzalez, F. J., and Tsutsui, M. (1996) Specificity of substrate and inhibitor probes for cytochrome P450s: Evaluation of in vitro metabolism using cDNA-expressed human P450s and human liver microsomes. Xenobiotica 26, 681-693.
37. Riess, W., Stierlin, H., Degen, P., Faigle, J. W., Gerardin, A., Moppert, J., Sallmann, A., Schmid, K., Schweizer, A., Sulc, M., Theobald, W., and Wagner, J. (1978) Pharmacokinetics and metabolism of the anti-inflammatory agent Voltaren. Scand. J. Rheumatol. Suppl., 17-29.
38. Sawchuk, R. J., Maloney, J. A., Cartier, L. L., Rackley, R. J., Chan, K. K. H., and Lau, H. S. L. (1995) Analysis of diclofenac and 4 of its metabolites in human urine by HPLC. Pharm. Res. 12, 756-762.
39. Godbillon, J., Gauron, S., and Metayer, J. P (1985) High-performance liquid chromatographic determination of diclofenac and its monohydroxylated metabolites in biological fluids. J. Chromatogr. 338, 151-159.
40. Dahlin, D. C., Miwa, G. T., Lu, A. Y. H., and Nelson, S. D. (1984) N-Acetyl-p-benzoquinone imine: a cytochrome P-450-mediated oxidation product of acetaminophen. Proc. Natl. Acad. Sci. U.S.A. 81, 1327-1331.
41. Dahlin, D. C., and Nelson, S. D. (1982) Synthesis, decomposition kinetics, and preliminary toxicological studies of pure N-acetyl-p-benzoquinone imine, a proposed toxic metabolite of acetaminophen. J. Med. Chem. 25, 885-886.
42. Jurimaromet, M., Crawford, K., and Huang, H. S. (1994) Comparative cytotoxicity of nonsteroidal antiinflammatory drugs in primary cultures of rat hepatocytes. Toxic. in Vitro 8, 55-66.
43. Schmitz, G., Lepper, H., and Estler, C. J. (1995) Failure of calcium antagonistic agents to prevent hepatotoxicity induced by diclofenac. Pharmacol. Toxicol. 77, 32-35.
44. Ponsoda, X., Bort, R., Jover, R., GomezLechon, M. J., and Castell, J. V. (1995) Molecular mechanism of diclofenac hepatotoxicity: association of cell injury with oxidative-metabolism and decrease in ATP levels. Toxic. in Vitro 9, 439-444.
45. Castell, J. V., GomezLechon, M. J., Ponsoda, X., and Bort, R. (1997) The use of cultured hepatocytes to investigate the mechanisms of drug hepatotoxicity. Cell Biol. Toxicol. 13, 331-338.
46. Pohl, L. R., Pumford, N. R., and Martin, J. L. (1996) Mechanisms, chemical structures and drug metabolism. Eur. J. Haematol. 57, 98-104.
47. Chang, T. K. H., Gonzalez, F. J., and Waxman, D. J. (1994) Evaluation of triacetyloleandomycin, α-naphthoflavone and diethyldithiocarbamate as selective chemical probes for inhibition of human cytochromes P450. Arch. Biochem. Biophys. 311, 437-442.
48. Liddle, C., Goodwin, B. J., George, J., Tapner, M., and Farrell, G. C. (1998) Separate and interactive regulation of cytochrome P450 3A4 by triiodothyronine, dexamethasone, and growth hormone in cultured hepatocytes. J. Clin. Endocrinol. Metab. 83, 2411-2416.
49. Miners, J. O., and Birkett, D. J. (1998) Cytochrome P4502C9: an enzyme of major importance in human drug metabolism. Br. J. Clin. Pharmacol. 45, 525-538.
50. Brune, K., and Lindner, J. (1992) Increased liver toxicity of diclofenac by paracetamol: results and possible mechanisms. In Side Effects of Antiinflammatory Drugs 3 (Rainsford, K. D., and Velo, G. P., Eds.) pp 198-203, Kluwer Academic Publishers, Boston, MA.
51. Miyamoto, G., Zahid, N., and Uetrecht, J. P. (1997) Oxidation of diclofenac to reactive intermediates by neutrophils, myeloperoxidase, and hypochlorous acid. Chem. Res. Toxicol. 10, 414-419.
52. Bougie, D., Johnson, S. T., Weitekamp, L. A., and Aster, R. H. (1997) Sensitivity to a metabolite of diclofenac as a cause of acute immune hemolytic anemia. Blood 90, 407-413.