Zafirlukast metabolism by cytochrome P450 3A4 produces an electrophilic α,β-unsaturated iminium species that results in the selective mechanism-based inactivation of the enzyme

Chemical Research in Toxicology

Volumn 18, Issue 9, 2005, Pages 1427-1437

  Kassahun, Kelem ^b   Skordos, Konstantine ^a   McIntosh, Ian ^b   Slaughter, Donald ^b   Doss, George A ^b   Baillie, Thomas A ^b   Yost, Garold S ^a  

^a UNIVERSITY OF UTAH   (United States)

^b MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ALCOHOL DERIVATIVE; CYTOCHROME P450 3A4; IMINE; IMINIUM; LEUKOTRIENE RECEPTOR BLOCKING AGENT; PEROXIDASE; UNCLASSIFIED DRUG; ZAFIRLUKAST;

ANIMAL CELL; ANIMAL TISSUE; ARTICLE; ASTHMA; BILE ACID METABOLISM; BIOTRANSFORMATION; DEHYDROGENATION; DRUG CROSS REACTIVITY; DRUG METABOLISM; ENZYME INACTIVATION; ENZYME MECHANISM; ENZYME METABOLISM; HUMAN; LIVER MICROSOME; LIVER TOXICITY; MASS SPECTROMETRY; NONHUMAN; NUCLEAR MAGNETIC RESONANCE; OXIDATION KINETICS; RAT;

ANIMALS; CYTOCHROME P-450 CYP3A; ENZYME ACTIVATION; GLUTATHIONE; HUMANS; HYDROXYLATION; IMINES; MAGNETIC RESONANCE SPECTROSCOPY; MASS SPECTROMETRY; MICROSOMES, LIVER; MOLECULAR STRUCTURE; PEROXIDASE; RATS; TIME FACTORS; TOSYL COMPOUNDS;

EID: 25444434659     PISSN: 0893228X     EISSN: None     Source Type: Journal    
DOI: 10.1021/tx050092b     Document Type: Article

References (26)

1. Reinus, J. F., Persky, S., Burkiewicz, J. S., Quan, D., Bass, N. M., and Davern, T. J (2000) Severe liver injury after treatment with the leukotriene receptor antagonist zafirlukast. Ann. Intern. Med. 133, 964-968.
2. Moles, J. R., Primo, J., Fernandez, J. M., and Hinojosa, J. E. (2001) Acute hepatocellular injury associated with zafirlukast. J. Hepatol. 35, 541-542.
3. Su, C. W., Wu, J. C., Huang, Y. H., Huang, Y. S., Chang, F. Y., and Lee, S. D. (2002) Zafirlukast-induced acute hepatitis. Zhonghua Yixue Zazhi (Taipei, Taiwan) 65, 553-556.
4. Nocerini, M. R., Carlson, J. R., and Yost, G. S. (1984) Electrophilic metabolites of 3-methylindole as toxic intermediates in pulmonary oedema. Xenobiotica 14, 561-564.
5. Nocerini, M. R., Yost, G. S., Carlson, J. R., Liberate, D. J., and Breeze, R. G. (1985) Structure of the glutathione adduct of activated 3-methylindole indicates that an imine methide is the electrophilic intermediate. Drug Metab. Dispos. 13, 690-694.
6. Skordos, K. W., Laycock, J. D., and Yost, G. S. (1998) Thioether adducts of a new imine reactive intermediate of the pneumotoxin 3-methylindole. Chem. Res. Toxicol. 11, 1326-1331.
7. Skordos, K. W., Skiles, G. L., Laycock, J. D., Lanza, D. L., and Yost, G. S. (1998) Evidence supporting the formation of 2,3-epoxy-3-methylindoline: a reactive intermediate of the pneumotoxin 3-methylindole. Chem. Res. Toxicol. 11, 741-749.
8. Skiles, G. L., and Yost, G. S. (1996) Mechanistic studies on the cytochrome P450-catalyzed dehydrogenation of 3-methylindole. Chem. Res. Toxicol. 9, 291-297.
9. Thornton-Manning, J., Appleton, M. L., Gonzalez, F. J., and Yost, G. S. (1996) Metabolism of 3-methylindole by vaccinia-expressed P450 enzymes: correlation of 3-methyleneindolenine formation and protein-binding. J. Pharmacol. Exp. Ther. 276, 21-29.
10. Regal, K. A., Laws, G. M., Yuan, C., Yost, G. S., and Skiles, G. L. (2001) Detection and characterization of DNA adducts of 3-methylindole. Chem. Res. Toxicol. 14, 1014-1024.
11. Racha, J. K., Rettie, A. E., and Kunze, K. L. (1998) Mechanism-based inactivation of human cytochrome P450 1A2 by furafylline: detection of a 1:1 adduct to protein and evidence for the formation of a novel imidazomethide intermediate. Biochemistry 37, 7407-7419.
12. Lanza, D. L., Code, E., Crespi, C. L., Gonzalez, F. J., and Yost, G. S. (1999) Specific dehydrogenation of 3-methylindole and epoxidation of naphthalene by recombinant human CYP2F1 expressed in lymphoblastoid cells. Drug Metab. Dispos. 27, 798-803.
13. Shader, R. I., Granda, B. W., von Moltke, L. L., Giancarlo, G. M., and Greenblatt, D. J. (1999) Inhibition of human cytochrome P450 isoforms in vitro by zafirlukast. Biopharm. Drug Dispos. 20, 385-388.
14. Liu, K. H., Lee, Y. M., Shon, J. H., Kim, M. J., Lee, S. S., Yoon, Y. R., Cha, I. J., and Shin, J. G. (2004) Potential of pranlukast and zafirlukast in the inhibition of human liver cytochrome P450 enzymes. Xenobiotica 34, 429-438.
15. Lu, P., Schrag, M., Slaughter, D., Raab, C., Shou, M., and Rodrigues, D. (2003) Mechanism-based inhibition of human liver microsomal cytochrome P450 1A2 by zileuton, a 5-lipoxygenase inhibitor. Drug Metab. Dispos. 31, 1352-1360.
16. Savidge, R. D., Bui, K. H., Birmingham, B. K., Morse, J. L., and Spreen, R. C. (1998) Metabolism and excretion of zafirlukast in dogs, rats, and mice. Drug Metab. Dispos. 26, 1069-1076.
17. th North American International Society for the Study of Xenobiotics Meeting, Oct 1996, San Diego, CA, p 392.
18. Kent, U. M., Juschyshyn, M. I., and Hollenberg, P. F. (2001) Mechanism-based inactivators as probes of cytochrome P450 structure and function. Curr. Drug Metab. 2, 215-243.
19. Bessems, J. G. M., de Groot, M. J., Baede, J. M., te Koppele, J. M., and Vermeulen, N. P. E. (1998) Hydrogen atom abstraction of 3,5-disubstituted analogues of paracetamol by horseradish peroxidase and cytochrome P450. Xenobiotica 28, 855-875.
20. Suttle, A. B., Birmingham, B. K., and Vargo, D. L. (1997) The pharmacokinetics of zafirlukast and terfenadine after administration to healthy men. Allergy 52 (Suppl. 37), 184.
21. Chung, K. F., and Barnes, P. J. (1998) Zafirlukast (ACCOLATE™). Drugs Today 34, 375-388.
22. Guengerich, F. P. (2001) Uncommon P450-catalyzed reactions. Curr. Drug Metab. 2, 93-115.
23. Raucy, J. L., Lasker, J. M., Lieber, C. S., and Black, M. (1989) Acetaminophen activation by human liver cytochromes CYPIIE1 and CYPIA2. Arch. Biochem. Biophys. 271, 270-283.
24. Bolton, J. L., and Thompson, J. A. (1991) Oxidation of butylated hydroxytoluene to toxic metabolites. Factors influencing hydroxylation and quinone methide formation by hepatic and pulmonary microsomes. Drug Metab. Dispos. 19, 467-472.
25. Lewis, M. A., Yoerg, D. G., Bolton, J. L., and Thompson, J. A. (1996) Alkylation of 2′-deoxynucleosides and DNA by quinone methides derived from 2,6-di-tert-butyl-4-methylphenol. Chem. Res. Toxicol. 9, 1368-1374.
26. Fan, P. W., Zhang, F., and Bolton, J. L. (2000) 4-Hydroxylated metabolites of the antiestrogens tamoxifen and toremifene are metabolized to unusually stable quinone methides. Chem. Res. Toxicol. 13, 45-52.