Characterization of cytochrome P450 isoforms involved in sequential two-step bioactivation of diclofenac to reactive p-benzoquinone imines

Toxicology Letters

Volumn 253, Issue , 2016, Pages 46-54

  den Braver, Michiel W ^a   den Braver Sewradj, Shalenie P ^a   Vermeulen, Nico P E ^a   Commandeur, Jan N M ^a  

^a VU UNIVERSITY AMSTERDAM   (Netherlands)

Author keywords

Bioactivation; Cytochrome P450; Diclofenac; Glutathione conjugates; Idiosyncratic liver injury; Reactive intermediates

Indexed keywords

1,4 BENZOQUINONE; CYTOCHROME P450; DICLOFENAC; DICLOFENAC 1',4' QUINONE IMINE; DICLOFENAC 2,5 QUINONE IMINE; UNCLASSIFIED DRUG; BENZOQUINONE DERIVATIVE; CYP2C9 PROTEIN, HUMAN; CYP3A4 PROTEIN, HUMAN; CYTOCHROME P450 2C9; CYTOCHROME P450 3A; GLUTATHIONE; IMINE; NONSTEROID ANTIINFLAMMATORY AGENT; QUINONE DERIVATIVE; RECOMBINANT PROTEIN;

AEROBIC METABOLISM; ARTICLE; CONCENTRATION RESPONSE; CONTROLLED STUDY; DEHYDROGENATION; ELECTROSPRAY; ENZYME ACTIVITY; HUMAN; HYDROXYLATION; INTRINSIC CLEARANCE; LIMIT OF DETECTION; MICHAELIS CONSTANT; OXIDATION; PRIORITY JOURNAL; SUBSTRATE CONCENTRATION; TURNOVER NUMBER; ENZYMOLOGY; KINETICS; LIVER MICROSOME; METABOLIC ACTIVATION; METABOLISM; OXIDATION REDUCTION REACTION; RISK ASSESSMENT;

ACTIVATION, METABOLIC; ANTI-INFLAMMATORY AGENTS, NON-STEROIDAL; BENZOQUINONES; CYTOCHROME P-450 CYP2C9; CYTOCHROME P-450 CYP3A; DICLOFENAC; GLUTATHIONE; HUMANS; HYDROXYLATION; IMINES; KINETICS; MICROSOMES, LIVER; OXIDATION-REDUCTION; RECOMBINANT PROTEINS; RISK ASSESSMENT;

EID: 84964543808     PISSN: 03784274     EISSN: 18793169     Source Type: Journal    
DOI: 10.1016/j.toxlet.2016.04.022     Document Type: Article

References (40)

1. Achour B., Barber J., Rostami-Hodjegan A. Expression of hepatic drug-metabolizing cytochrome P450 enzymes and their intercorrelations: a meta-analysis. Drug Metab. Dispos. 2014, 42:1349-1356.
2. Aithal G.P., Day C.P., Leathart J.B., Daly A.K. Relationship of polymorphism in CYP2C9 to genetic susceptibility to diclofenac-induced hepatitis. Pharmacogenetics 2000, 10:511-518.
3. Aithal G.P. Diclofenac-induced liver injury: a paradigm of idiosyncratic drug toxicity. Expert Opin. Drug Saf. 2004, 3:519-523.
4. Banks A.T., Zimmerman H.J., Ishak K.G., Harter J.G. Diclofenac-associated hepatotoxicity: analysis of 180 cases reported to the Food and Drug Administration as adverse reactions. Hepatology 1995, 22:820-827.
5. Boelsterli U.A. Diclofenac-induced liver injury: a paradigm of idiosyncratic drug toxicity. Toxicol. Appl. Pharmacol. 2003, 192:307-322.
6. Boerma J.S., Dragovic S., Vermeulen N.P.E., Commandeur J.N.M. Mass spectrometric characterization of protein adducts of multiple P450-dependent reactive intermediates of diclofenac to human glutathione-S-transferase P 1-1. Chem. Res. Toxicol. 2012, 25:2532-2541.
7. Boerma J.S., Vermeulen N.P.E., Commandeur J.N.M. One-electron oxidation of diclofenac by human cytochrome P450s as a potential bioactivation mechanism for formation of 2'-(glutathion-S-yl)-deschloro-diclofenac. Chem. Biol. Interact. 2014, 207:32-40.
8. Bort R., Macé K., Boobis A., Gómez-Lechón M.J., Pfeifer A., Castell J. Hepatic metabolism of diclofenac: role of human CYP in the minor oxidative pathways. Biochem. Pharmacol. 1999, 58:787-796.
9. Daly A.K., Aithal G.P., Leathart J.B.S., Swainsbury R.A., Dang T.S., Day C.P. Genetic susceptibility to diclofenac-induced hepatotoxicity: contribution of UGT2B7, CYP2C8, and ABCC2 genotypes. Gastroenterology 2007, 132:272-281.
10. Dragovic S., Boerma J.S., Vermeulen N.P.E., Commandeur J.N.M. Effect of human glutathione S-transferases on glutathione-dependent inactivation of cytochrome P450-dependent reactive intermediates of diclofenac. Chem. Res. Toxicol. 2013, 26:1632-1641.
11. Gan T.J. Diclofenac: an update on its mechanism of action and safety profile. Curr. Med. Res. Opin. 2010, 26:1715-1731.
12. Hammond T.G., Meng X., Jenkins R.E., Maggs J.L., Castelazo A.S., Regan S.L., Bennett S.N.L., Earnshaw C.J., Aithal G.P., Pande I., Kenna J.G., Stachulski A., Park B.K., Williams D.P. Mass spectrometric characterization of circulating covalent protein adducts derived from a drug acyl glucuronide metabolite: multiple albumin adductions in diclofenac patients. J. Pharmacol. Exp. Ther. 2014, 350:387-402.
13. Helfgott S.M. Diclofenac-associated hepatotoxicity. J. Am. Med. Assoc. 1990, 264:2660.
14. Kishida T., Onozato T., Kanazawa T., Tanaka S., Kuroda J. Increase in covalent binding of 5-hydroxydiclofenac to hepatic tissues in rats co-treated with lipopolysaccharide and diclofenac: involvement in the onset of diclofenac-induced idiosyncratic hepatotoxicity. J. Toxicol. Sci. 2012, 37:1143-1156.
15. Koga T., Fujiwara R., Nakajima M., Yokoi T. Toxicological evaluation of acyl glucuronides of nonsteroidal anti-inflammatory drugs using human embryonic kidney 293Cells stably expressing human UDP-glucuronosyltransferase and human hepatocytes. Pharmacology 2011, 54-60.
16. Kretz-Rommel A., Boelsterli U.A. 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. 1993, 120:155-161.
17. Kumar S., Samuel K., Subramanian R., Braun M.P., Stearns R.A., Chiu S.-H.L., Evans D.C., Baillie T.A. Extrapolation of diclofenac clearance from in vitro microsomal metabolism data: role of acyl glucuronidation and sequential oxidative metabolism of the acyl glucuronide. J. Pharmacol. Exp. Ther. 2002, 303:969-978.
18. Lahoz A., Vilà M.R., Fabre M., Miquel J.M., Rivas M., Maines J., Castell J.V., Gómez-lechón M.J. An in vitro tool to assess cytochrome P450 drug biotransformation-dependent cytotoxicity in engineered HepG2 cells generated by using adenoviral vectors. Toxicol. Vitro 2013, 27:1410-1415.
19. Laine L., Goldkind L., Curtis S.P., Connors L.G., Yanqiong Z., Cannon C.P. How common is diclofenac-associated liver injury? Analysis of 17,289 arthritis patients in a long-term prospective clinical trial. Am. J. Gastroenterol. 2009, 104:356-362.
20. Leemann T., Transon C., Dayer P. Cytochrome P450TB (CYP2C): a major monooxygenase catalyzing diclofenac 4'-hydroxylation in human liver. Life Sci. 1993, 52:29-34.
21. Li A.P. A review of the common properties of drugs with idiosyncratic hepatotoxicity and the multiple determinant hypothesis for the manifestation of idiosyncratic drug toxicity. Chem. Biol. Interact. 2002, 142:7-23.
22. McGettigan P., Henry D. Use of non-Steroidal anti-Inflammatory drugs that elevate cardiovascular risk: an examination of sales and essential medicines lists in low-, middle-and high-income countries. PLoS Med. 2013, 10.
23. Naisbitt D.J., Sanderson L.S., Meng X., Stachulski A.V., Clarke S.E., Park B.K. Investigation of the immunogenicity of diclofenac and diclofenac metabolites. Toxicol. Lett. 2007, 168:45-50.
24. Ramsden D., Tweedie D.J., Chan T.S., Tracy T.S. Altered CYP2C9 activity following modulation of CYP3A4 levels in human hepatocytes: an example of protein-Protein interactions. Drug Metab. Dispos. 2014, 42:1940-1946.
25. Shen S., Marchick M.R., Davis M.R., Doss G.A., Pohl L.R. Metabolic activation of diclofenac by human cytochrome P450 3A4: role of 5-hydroxydiclofenac. Chem. Res. Toxicol. 1999, 12:214-222.
26. Stephens C., Andrade R.J., Lucena M.I. Mechanisms of drug-induced liver injury. Curr. Opin. Allergy Clin. Immunol. 2014, 14:286-292.
27. Subramanian M., Low M., Locuson C.W., Tracy T.S. CYP2D6-CYP2C9 protein-protein interactions and isoform-selective effects on substrate binding and catalysis. Drug Metab. Dispos. 2009, 37:1682-1689.
28. Subramanian M., Tam H., Zheng H., Tracy T.S. CYP2C9-CYP3A4 protein-protein interactions: role of the hydrophobic N terminus. Drug Metab. Dispos. 2010, 38:1003-1009.
29. Tang W., Stearns R.A., Bandiera S.M., Zhang Y., Raab C., Braun M.P., Dean D.C., Pang J., Leung K.H., Doss G.A., Strauss J.R., Kwei G.Y., Rushmore T.H., Chiu S.H., Baillie T.A. Studies on cytochrome P-450-mediated bioactivation of diclofenac in rats and in human hepatocytes: identification of glutathione conjugated metabolites. Drug Metab. Dispos. 1999, 27:365-372.
30. Tang W., Stearns R.A., Wang R.W., Chiu S.H., Baillie T.A. Roles of human hepatic cytochrome P450s 2C9 and 3A4 in the metabolic activation of diclofenac. Chem. Res. Toxicol. 1999, 12:192-199.
31. Tolosa L., Gomez-lechon J., Perez-Cataldo G., Castell J.V., Donato M.T. HepG2 cells simultaneously expressing five P450 enzymes for the screening of hepatotoxicity: identification of bioactivable drugs and the potential mechanism of toxicity involved. Arch. Toxicol. 2013, 87:1115-1127.
32. Uetrecht J. Idiosyncratic drug reactions: current understanding. Annu. Rev. Pharmacol. Toxicol. 2007, 47:513-539.
33. Urban T.J., Shen Y., Stolz A., Chalasani N., Fontana R.J., Rochon J., Ge D., Shianna K.V., Daly A.K., Lucena M.I., Nelson M.R., Molokhia M., Aithal G.P., Floratos A., Pe'er I., Serrano J., Bonkovsky H., Davern T.J., Lee W.M., Navarro V.J., Talwalkar J.A., Goldstein D.B., Watkins P.B. Limited contribution of common genetic variants to risk for liver injury due to a variety of drugs. Pharmacogenet. Genomics 2012, 22:784-795.
34. Vredenburg G., Elias N.S., Venkataraman H., Hendriks D.F.G., Vermeulen N.P.E., Commandeur J.N.M., Vos J.C. Human NAD(P)H: quinone oxidoreductase 1 (NQO1)-mediated inactivation of reactive quinoneimine metabolites of diclofenac and mefenamic acid. Chem. Res. Toxicol. 2014, 27:576-586.
35. Wang H., Yuan L., Zeng S. Characterizing the effect of UDP-glucuronosyltransferase (UGT) 2B7 and UGT1A9 genetic polymorphisms on enantioselective glucuronidation of flurbiprofen. Biochem. Pharmacol. 2011, 82:1757-1763.
36. Yamazaki H., Gillam E.M., Dong M.S., Johnson W.W., Guengerich F.P., Shimada T. Reconstitution of recombinant cytochrome P450 2C10(2C9) and comparison with cytochrome P450 3A4 and other forms: effects of cytochrome P450-P450 and cytochrome P450-b5 interactions. Arch. Biochem. Biophys. 1997, 342:329-337.
37. Yu L.J., Chen Y., Deninno M.P., O'Connell T.N., Hop C.E. Identification of a novel glutathione adduct of diclofenac, 4'-hydroxy-2'-glutathion-deschloro-diclofenac, upon incubation with human liver microsomes. Drug Metab. Dispos. 2005, 33:484-488.
38. Zanger U.M., Klein K., Thomas M., Rieger J.K., Tremmel R., Kandel B.A., Klein M., Magdy T. Genetics, epigenetics, and regulation of drug-metabolizing cytochrome p450 enzymes. Clin. Pharmacol. Ther. 2014, 95:258-261.
39. de Abajo F.J., Montero D., Madurga M., Rodriguez L.A.G. Acute and clinically relevant drug-induced liver injury: a population based case-control study. Br. J. Clin. Pharmacol. 2004, 58:71-80.
40. Zhu Y., Zhang Q.-Y. Role of intestinal cytochrome p450 enzymes in diclofenac-induced toxicity in the small intestine. J. Pharmacol. Exp. Ther. 2012, 343:362-370.