Bioactivation of a dihydropyrazole-1-carboxylic acid-(4-chlorophenyl amide) scaffold to a putative p-chlorophenyl isocyanate in rat liver microsomes and in vivo in rats

Chemical Research in Toxicology

Volumn 21, Issue 5, 2008, Pages 1095-1106

  Chen, Hao ^a   Zhang, Yanhua ^a   Edmunds, Jeremy ^a   Bigge, Christopher ^a   Mutlib, Abdul ^a  

^a PFIZER INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

4 CHLOROPHENYLANILINE; 4 CHLOROPHENYLISOCYANATE; 4,5 DIHYDROPYRAZOLE 1,5 DICARBOXYLIC ACID 1 [(4 CHLOROPHENYL)AMIDE] 5 [(2 OXO 2H [1,3']BIPYRIDINYL 6' YL)AMIDE]; ANILINE DERIVATIVE; CARBOXYLIC ACID DERIVATIVE; CYTOCHROME P450; CYTOCHROME P450 1A; CYTOCHROME P450 2C; CYTOCHROME P450 3A; GLUTATHIONE; ISOCYANIC ACID DERIVATIVE; PYRAZOLINE DERIVATIVE; REDUCED NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE; CHLOROBENZENE; CHLOROPHENYL ISOCYANATE; DIHYDROPYRAZOLE 1 CARBOXYLIC ACID (4 CHLOROPHENYL AMIDE); DIHYDROPYRAZOLE-1-CARBOXYLIC ACID-(4-CHLOROPHENYL AMIDE); PYRAZOLE DERIVATIVE;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL TISSUE; ARTICLE; BILE; BILE FLOW; CARBAMOYLATION; CHEMICAL STRUCTURE; CONTROLLED STUDY; COVALENT BOND; ELECTROCHEMICAL ANALYSIS; GLUTATHIONE METABOLISM; HUMAN; HUMAN CELL; HYDROXYLATION; IN VITRO STUDY; IN VIVO STUDY; LIQUID CHROMATOGRAPHY; LIVER MICROSOME; MACROMOLECULE; MALE; NONHUMAN; RAT; TANDEM MASS SPECTROMETRY; URINALYSIS; ANIMAL; CHEMISTRY; DRUG EFFECT; ENZYME ACTIVATION; KINETICS; MASS SPECTROMETRY; METABOLISM;

RATTUS;

ANIMALS; CHLOROBENZENES; CYTOCHROME P-450 ENZYME SYSTEM; ENZYME ACTIVATION; GLUTATHIONE; HUMANS; ISOCYANATES; KINETICS; MALE; MASS SPECTROMETRY; MICROSOMES, LIVER; MOLECULAR STRUCTURE; PYRAZOLES; RATS;

EID: 47549091948     PISSN: 0893228X     EISSN: None     Source Type: Journal    
DOI: 10.1021/tx7004019     Document Type: Article

References (35)

1. Kola, I., and Landis, J. (2004) Can the pharmaceutical industry reduce attrition rates? Nat. Rev. Drug Discovery 3, 711-716.
2. Hinson, J. A., Pumford, N. R., and Nelson, S. D. (1994) The role of metabolic activation in drug toxicity. Drug Metab. Rev. 26, 395-112.
3. Hinson, J. A., Pumford, N. R., and Roberts, D. W. (1995) Mechanisms of acetaminophen toxicity: Immunochemical detection of drug-protein adducts. Drug Metab. Rev. 27, 73-92.
4. Williams, D. P., Pirmohamed, M., Naisbitt, D. J., Maggs, J. L., and Park, B. K. (1997) Neutrophil cytotoxicity of the chemically reactive metabolite(s) of clozapine: Possible role in agranulocytosis. J. Pharmacol. Exp. Ther. 283, 1375-1382.
5. Koen, Y. M., and Hanzlik, R. P. (2002) Identification of seven proteins in the endoplasmic reticulum as targets for reactive metabolites of bromobenzene. Chem. Res. Toxicol. 15, 699-706.
6. Baillie, T. A., and Kassahun, K. (2001) Biological reactive intermediates in drug discovery and development: A perspective from the pharmaceutical industry. Adv. Exp. Med. Biol. 500, 45-71.
7. Park, B. K., Kitteringham, N. P., Maggs, J. L., Pirmohamed, M., and Williams, D. P. (2004) The role of metabolic activation in drug-induced hepatotoxicity. Annu. Rev. Pharmacol. Toxicol. 45, 177-202.
8. Baillie, T. A. (2006) Future of toxicology-metabolic activation and drug design: Challenges and opportunities in chemical toxicology. Chem. Res. Toxicol. 19, 889-892.
9. Dahlin, D. C., Miwa, G. T., Lu, A. Y., and Nelson, S. D. (1984) N-Acetyl-p-benzoquinone imine: A cytochrome P450-mediated oxidation product of acetaminophen. Proc. Natl. Acad. Sci. U.S.A. 81, 1327-1331.
10. Holme, J. A., Dahlin, D. C., Nelson, S. D., and Dybing, E. (1984) Cytotoxic effects of N-acetyl-p-benzoquinone imine, a common arylating intermediate of paracetamol and N-hydroxyparacetamol. Biochem. Pharmacol. 33, 401-406.
11. Lu, A. Y., Miwa, G. T., and Wislocki, P. G. (1988) Toxicological significance of covalently bound drug residue. Rev. Biochem. Toxicol. 9, 1-27.
12. Tirmenstein, M. A., and Nelson, S. D. (1989) Subcellular binding and effects on calcium homeostasis produced by acetaminophen and a nonhepatotoxic regioisomer, 3′-hydroxyacetanilide, in mouse liver. J. Biol. Chem. 264, 9814-9819.
13. Hinson, J. A., and Roberts, D. W. (1992) Role of covalent and noncovalent interactions in cell toxicity: Effects on proteins. Annu. Rev. Pharmacol. Toxicol. 32, 471-510.
14. Nelson, S. D. (1995) Mechanisms of the formation and disposition of reactive metabolites that can cause acute liver injury. Drug Metab. Rev. 27, 147-177.
15. Evans, D. C., Watt, A. P., Nicoll-Griffith, D. A., and Baillie, T. A. (2004) Drug-protein adducts: An industry perspective on minimizing the potential for drug bioactivation in drug discovery and development. Chem. Res. Toxicol. 17, 3-16.
16. Yan, Z., and Caldwell, G. W. (2004) Stable-isotope trapping and high-throughput screenings of reactive metabolites using the isotope MS signature. Anal. Chem. 76, 6835-6847.
17. Gan, J., Harper, T. W., Hsueh, M.-M., Qu, Q., and Humphreys, G. W. (2005) Dansyl glutathione as a trapping agent for the quantitative estimation and identification of reactive metabolites. Chem. Res. Toxicol. 18, 896-903.
18. Castro-Perez, J., Plumb, R., Liang, L., and Yang, E. (2005) A high-throughput liquid chromatography/tandem mass spectrometry method for screening glutathione conjugates using exact mass neutral loss acquisition. Rapid Commun. Mass Spectrom. 19, 798-804.
19. Mutlib, A., Lam, W., Atherton, J., Chen, H., Galatsis, P., and Stolle, W. (2005) Application of stable isotope labeled glutathione and rapid scanning mass spectrometers in detecting and characterizing reactive metabolites. Rapid Commun. Mass Spectrom. 19, 3482-3492.
20. Chen, H., Zientek, M., Jalaie, M., Bigge, C., and Mutlib, A. E. (2008) P450 3A4-dependent bioactivation of a compound containing a dihydropyrazole-1- carboxylic acid-[(4-chlorophenyl)-amide] motif to a putative chlorophenyl isocyanate intermediate in human liver microsomes, manuscript in preparation.
21. Jochheim, C. M., Davis, M. R., Baillie, K. M., Ehlhardt, W. J., and Baillie, T. A. (2002) Glutathione-dependent metabolism of the antitumor agent sulofenur. Evidence for the formation of p-chlorophenyl isocyanate as a reactive intermediate. Chem. Res. Toxicol. 15, 240-248.
22. Chen, H., Zhang, Y.-H., Mutlib, A. E., and Zhong, M. (2006) Application of on-line electrochemical derivatization coupled with high performance liquid chromatography electrospray ionization mass spectrometry for detection and quantitation of (p-chlorophenyl) aniline in biological samples. Anal. Chem. 78, 2413-2421.
23. Baillie, T. A., and Davis, M. R. (1993) Mass spectrometry in the analysis of glutathione conjugate. Biol. Mass Spectrom. 22, 319-325.
24. Chang, T., Levine, M., and Bellward, G. D. (1992) Selective inhibition of rat hepatic microsomal cytochrome P450. Effect of the in vitro administration of cimetidine. Drug Metab. Dispos. 260, 1450-1455.
25. Guengerich, F. P., Dannan, G. A., Wright, S. T., Martin, M. V., and Kaminski, L. S. (1982) Purification and characterization of liver microsomal cytochrome P450: Electrophoretic, spectral, catalytic and immunochemical properties and inducibility of eight isoeymes isolated from rats treated with phenobarbital and α-naphthoflavone. Biochemistry 21, 6019-6031.
26. Cooper, K. O., Reik, L. M., Jayyosi, Z., Bandiera, S., Kelley, M., Ryan, D. E., Daniel, R., McCluskey, S. A., Levin, W., and Thomas, P. E. (1993) Regulation of two members of the steroid-inducible cytochrome P450 subfamily (3A) in rats. Arch. Biochem. Biophys. 301, 345-354.
27. Hutzler, M. J., and Tracy, T. (2002) Atypical kinetic profiles in drug metabolism reactions. Drug Metab. Dispos. 30, 355-362.
28. Mutlib, A. E., Talaat, R. E., Slatter, J. G., and Abbott, F. S. (1990) Formation and reversibility of S-linked conjugates of N-(1-methyl-3,3 diphenylpropyl) isocyanate, an in vivo metabolite of N-(1-methyl-3,3- diphenylpropyl) formamaide, in rats. Drug Metab. Dispos. 18, 1038-1045.
29. Baillie, T. A., and Slatter, J. G. (1991) Glutathione: A vehicle for the transport of chemically reactive metabolites in vivo. Acc. Chem. Res. 24, 264-270.
30. Baillie, T. A., and Kassahun, K. (1994) Reversibility in glutathione-conjugate formation. Adv. Pharmacol. 27, 163-181.
31. Brown, W. E., Green, A. H., Cedel, T. E., and Cairns, J. (1987) Biochemistry of protein-isocyanate interactions: A comparison of the effects of aryl vs. alkyl isocyanates. Environ. Health Perspect. 72, 5-11.
32. Gold, L. S., Manley, N. B., Slowe, T. H., Garfinkel, G. B., Rohrbach, L., and Ames, B. N. (1993) The fifth plot of the carcinogengenic potency database: Results of animal bioassays published in general literature through 1988 and by the national toxicology program through 1989. Environ. Health Perspect. 100, 65-168.
33. Nagasawa, H. T., Smith, W. E., and Kwon, C.-H. (1985) Acetylative cleavage of (arylsulfonyl) ureas to N-acetyl arenesulfonamides and isocyanate. J. Org. Chem. 50, 4993-4996.
34. Davis, M. R., Kassahun, K., Jochheim, C. M., Brandt, K., and Baillie, T. A. (1993) Glutathione and N-acetylcysteine conjugates of 2-chloroethyl isocyanate. Identification as metabolites of N,N′-bis(2- chloroethyl)-N-nitrosourea in the rat and inhibitory properties toward glutathione reductase in vivo. Chem. Res. Toxicol. 6, 376-383.
35. Guan, X., Hoffman, B. N., McFarland, D. C., Gilkerson, K. K., Dwivedi, C., Erickson, A. K., Bebensee, S., and Pellegrini, J. (2002) Glutathione and mercapturic acid conjugates of sulofenur and their activity against a human colon cancer cell line. Drug Metab. Dispos. 30, 331-335.