Skip to main content

Metabolic Concerns in Drug Design

  • Chapter
  • First Online:
Advances in Bioactivation Research

Part of the book series: Biotechnology: Pharmaceutical Aspects ((PHARMASP,volume IX))

  • 658 Accesses

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Arimoto, R. 2006. Computational models for predicting interactions with cytochrome p450 enzyme. Curr. Top. Med. Chem. 6:1609–1618.

    Article  PubMed  CAS  Google Scholar 

  • Atkins, W. M., and Sligar, S. G. 1987. Metabolic switching in cytochrome P-450cam: Deuterium isotope effects on regiospecificity and the monooxygenase/oxidase ratio. J. Am. Chem. Soc. 109:3754–3760.

    Article  CAS  Google Scholar 

  • Berg, A., Ingelman-Sundberg, M., and Gustafsson, J. A. 1979. Purification and characterization of cytochrome P-450 meg. J. Biol. Chem. 254(12):5264–5271.

    PubMed  CAS  Google Scholar 

  • Blobaum, A. L., Kent, U. M., Alworth, W. L., and Hollenberg, P. F. 2004. Novel reversible inactivation of cytochrome P450 2E1 T303A by tert-butyl acetylene: the role of threonine 303 in proton delivery to the active site of cytochrome P450 2E1. J. Pharmacol. Exp. Ther. 310(1):281–290.

    Article  PubMed  CAS  Google Scholar 

  • Caron, G., Ermondi G., and Testa, B. 2007. Predicting the oxidative metabolism of statins: An application of the MetaSite (R) algorithm. Pharm. Res. 24(3):480–501.

    Article  PubMed  CAS  Google Scholar 

  • Chandrasena, R. E. P., Vatsis, K. P., Coon, M. J., Hollenberg, P. F., and Newcomb, M. 2004. Hydroxylation by the hydroperoxy-iron species in cytochrome P450 enzymes. J. Am. Chem. Soc. 126(1):115–126.

    Article  PubMed  CAS  Google Scholar 

  • Cho, K. Y., Moreau, Y., Kumar, D., Rock, D. A., Jones, J. P., and Shaik, S. 2007. Formation of the active species of cytochrome P450 by using iodosylbenzene: A case for spin-selective reactivity. Chemistry: A European Journal: Published Online.

    Google Scholar 

  • Cohen, S., Kozuch, S., Hazan, C., and Shaik, S. 2006. Does substrate oxidation determine the regioselectivity of cyclohexene and propene oxidation by cytochrome P450? J. Am. Chem. Soc. 128:11028–11029.

    Article  PubMed  CAS  Google Scholar 

  • Coon, M. J., and Vaz, A. D. 1988. Role of cytochrome P-450 in hydrocarbon formation from xenobiotic and lipid hydroperoxides. Prog. Clin. Biol. Res. 274:497–507.

    PubMed  CAS  Google Scholar 

  • Cruciani, G., Carosati, E., De Boeck, B., Ethirajulu, K., Mackie, C., Howe, T., and Vianello, R. 2005. MetaSite: Understanding metabolism in human cytochromes from the perspective of the chemist. J. Med. Chem. 48:6970–6979.

    Article  PubMed  CAS  Google Scholar 

  • Cryle, M. J., and De Voss, J. J. 2006. Is the ferric hydroperoxy species responsible for sulfur oxidation in cytochrome P450s. Angewandte Chemie-International Edition 45: 8221–8223.

    Article  CAS  Google Scholar 

  • Davydov, R., Perera, R., Jin, S. X., Yang, T. C., Bryson, T. A., Sono, M., Dawson J. H., and Hoffman, B. M. 2005. Substrate modulation of the properties and reactivity of the oxy-ferrous and hydroperoxo-ferric intermediates of cytochrome P450cam as shown by cryoreduction-EPR/ENDOR spectroscopy. J. Am. Chem. Soc. 127:1403–1413.

    Article  PubMed  CAS  Google Scholar 

  • Denisov, I. G., Makris, T. M., and Sligar, S. G. 2001. Cryotrapped reaction intermediates of cytochrome p450 studied by radiolytic reduction with phosphorus-32. J. Biol. Chem. 276:11648–11652.

    Article  PubMed  CAS  Google Scholar 

  • Dimasi, J. A. 2001. New drug development in the United States from 1963 to 1999. Clin. Pharmacol. Ther. 69:286–296.

    Article  PubMed  CAS  Google Scholar 

  • Dowers, T. S., and Jones, J. P. 2006. Kinetic isotope effects implicate a single oxidant for cytochrome P450-mediated O-dealkylation, N-oxygenation, and aromatic hydroxylation of 6-methoxyquinoline. Drug Metab. Dispos. 34:1288–1290.

    Article  PubMed  CAS  Google Scholar 

  • Dowers, T. S., Rock, D. A., Rock, D. A., and Jones, J. P. 2004a. Kinetic isotope effects implicate the iron-oxene as the sole oxidant in P450-catalyzed N-dealkylation. J. Am. Chem. Soc. 126:8868–8869.

    Article  CAS  Google Scholar 

  • Dowers, T. S., Rock, D. A., Rock, D. A., Perkins, B. N. S., and Jones, J. P. 2004b. An analysis of the regioselectivity of aromatic hydroxylation and N-oxygenation by cytochrome P450 enzymes. Drug Metab. Dispos. 32:328–332.

    Article  CAS  Google Scholar 

  • Ekins, S., Berbaum, J., and Harrison, R. K. 2003. Generation and validation of rapid computational filters for CYP2D6 and CYP3A4. Drug Metab. Dispos. 31:1077–1080.

    Article  PubMed  CAS  Google Scholar 

  • Fisher, R., Brendel, K., and Hanzlik, R. P. 1993. Correlation of metabolism, covalent binding and toxicity for a series of bromobenzene derivatives using rat liver slices in vitro. Chem. Biol. Interact. 88:191–198.

    Article  PubMed  CAS  Google Scholar 

  • French, K. J., Strickler, M. D., Rock, D. A., Rock, D. A., Bennett, G. A., Wahlstrom, J. L., Goldstein, B. M., and Jones, J. P. 2001. Benign synthesis of 2-ethylhexanoic acid by cytochrome P450cam: Enzymatic, crystallographic, and theoretical studies. Biochemistry 40:9532–9538.

    Article  PubMed  CAS  Google Scholar 

  • Gonzalez, F. J. 1992. Human cytochrome P450: problems and prospects. TiPs Reviews 13:346–352.

    CAS  Google Scholar 

  • Grogan, J., DeVito, S. C., Pearlman, R. S., and Korzekwa, K. R. 1992. Modeling cyanide release from nitriles: Prediction of cytochrome P450 mediated acute nitrile toxicity. Chem. Res. Toxicol. 5:548–552.

    Article  PubMed  CAS  Google Scholar 

  • Groves, J. T., McClusky, G. A., White, R. E., and Coon, M. J. 1978. Aliphatic hydroxylation by highly purified liver microsomal cytochrome P450. Evidence for a carbon radical intermediate. Biochem. Biophys. Res. Commun. 81:154–160.

    Article  PubMed  CAS  Google Scholar 

  • Guengerich, F. P., Yun C., and MacDonald, T. L. 1996. Evidence for a 1-electron oxidation mechanism in N-dealkylation of N,N-dialkylanilines by cytochrome P450 2B1. J. Biol. Chem. 271:27321–27329.

    Article  PubMed  CAS  Google Scholar 

  • Harris, J. W., Jones, J. P., Martin, J. L., LaRosa, A. C., Olson, M. J., Pohl, L. R., and Anders, M. W. 1992. Pentahaloethane-based chlorofluorocarbon substitutes and halothane: Correlation of in vivo hepatic protein-trifluoroacetylation and urinary trifluoroacetic acid excretion with calculated enthalpies of activation. Chem. Res. Toxicol. 5:720–725.

    Article  PubMed  CAS  Google Scholar 

  • He, M., Korzekwa, K. R., Jones, J. P., Rettie, A. E., and Trager, W. F. 1999. Structural forms of phenprocoumon and warfarin that are metabolized at the active site of CYP2C9. Arch. Biochem. Biophys. 372:16–28.

    Article  PubMed  CAS  Google Scholar 

  • Higgins, L., Bennett, G. A., Shimoji, M., and Jones, J. P. 1998. Evaluation of cytochrome P450 mechanism and kinetics using kinetic deuterium isotope effects. Biochemistry 37:7039–7046.

    Article  PubMed  CAS  Google Scholar 

  • Higgins, L., Korzekwa, K. R., Rao, S., Shou, M., and Jones, J. P. 2001. An assessment of the reaction energetics for cytochrome P450-mediated reactions. Arch. Biochem. Biophys. 385:220–230.

    Article  PubMed  CAS  Google Scholar 

  • Hirao, H., Kumar, D., and Shaik, S. 2006. On the identity and reactivity patterns of the “second oxidant” of the T252A mutant of cytochrome P450(cam) in the oxidation of 5-methylenenylcamphor. J. Inorg. Biochem. 100:2054–2068.

    Article  PubMed  CAS  Google Scholar 

  • Hudelson, M. G., and Jones, J. P. 2006. Line-walking method for predicting the inhibition of P450 drug metabolism. J. Med. Chem. 49:4367–4373.

    Article  PubMed  CAS  Google Scholar 

  • Hummel, M. A., Tracy, T. S., Hutzler, J. M., Wahlstrom, J. L., Zhou Y., and Rock, D. A. 2006. Influence of fluorescent probe size and cytochrome b5 on drug–drug interactions in CYP2C9. J. Biomol. Screen. 11:303–309.

    Article  PubMed  CAS  Google Scholar 

  • Hutzler, J. M., Powers, F. J., Wynalda, M. A., and Wienkers, L. C. 2003. Effect of carbonate anion on cytochrome P450 2D6-mediated metabolism in vitro: the potential role of multiple oxygenating species. Arch. Biochem. Biophys. 417:165–175.

    Article  PubMed  CAS  Google Scholar 

  • Jankel, C. A., McMillan, J. A., and Martin, B. C. 1994. Effect of drug interactions on outcomes of patients receiving warfarin or theophylline. Am. J. Hosp. Pharm. 51:661–666.

    PubMed  CAS  Google Scholar 

  • Jensen, B. F., Vind, C., Padkjaer, S. B., Brockhoff, P. B., and Refsgaard, H. H. 2007. In silico prediction of cytochrome P450 2D6 and 3A4 inhibition using Gaussian kernel weighted k-nearest neighbor and extended connectivity fingerprints, including structural fragment analysis of inhibitors versus noninhibitors. J. Med. Chem. 50:501–511.

    Article  PubMed  CAS  Google Scholar 

  • Jin, S., Makris, T. M., Bryson, T. A., Sligar, S. G., and Dawson, J. H. 2003. Epoxidation of olefins by hydroperoxo-ferric cytochrome P450. J. Am. Chem. Soc. 125:3406–3407.

    Article  PubMed  CAS  Google Scholar 

  • Jin, S. X., Bryson, T. A., and Dawson, J. H. 2004. Hydroperoxoferric heme intermediate as a second electrophilic oxidant in cytochrome P450-catalyzed reactions. J. Biol. Inorg. Chem. 9:644–653.

    Article  PubMed  CAS  Google Scholar 

  • Jones, J. P. 2004. Metabolic menages a trois: what does it mean for drug design? Drug Discov. Today 9:592–592.

    Article  PubMed  Google Scholar 

  • Jones, J. P., Korzekwa, K. R., Rettie, A. E., and Trager, W. F. 1986. Isotopically sensitive branching and its effect on the observed intramolecular isotope effects in cytochrome P450 catalyzed reactions: a new method for the estimation of intrinsic isotope effects. J. Am. Chem. Soc. 108:7074–7078.

    Article  CAS  Google Scholar 

  • Jones, J. P., Mysinger, M., and Korzekwa, K. R. 2002. Computational models for cytochrome P450: a predictive electronic model for aromatic oxidation and hydrogen atom abstraction. Drug Metab. Dispos. 30:7–12.

    Article  PubMed  CAS  Google Scholar 

  • Jones, J. P., Rettie, A. E., and Trager, W. F. 1990. Intrinsic isotope effects suggest that the reaction coordinate symmetry for the cytochrome P450 catalyzed hydroxylation of octane is isozyme independent. J. Med. Chem. 33:1242–1246.

    Article  PubMed  CAS  Google Scholar 

  • Kamachi, T., Shiota, Y., Ohta, T., and Yoshizawa, K. 2003. Does the hydroperoxo species of cytochrome P450 participate in olefin epoxidation with the main oxidant, Cpd I? Criticism from density functional theory calculations. Bull. Chem. Soc. Jpn. 76:721–732.

    Article  CAS  Google Scholar 

  • Karki, S., Dinnocenzo, J. P., Jones, J. P., and Korzekwa, K. R. 1995. Mechanism of oxidative amine dealkylation of substituted N,N-dimethylanilines by cytochrome P-450 – application of isotope effect profiles. J. Am. Chem. Soc. 117:3657–3664.

    Article  CAS  Google Scholar 

  • Keizers, P. H. J., Schraven, L. H. M., de Graaf, C., Hidestrand, M., Ingelman-Sundberg, M., van Dijk, B. R., Vermeulen, N. P. E., and Commandeur, J. N. M. 2005. Role of the conserved threonine 309 in mechanism of oxidation by cytochrome P450 2D6. Biochem. Biophys. Res. Commun. 338:1065–1074.

    Article  PubMed  CAS  Google Scholar 

  • Korhonen, L. E., Turpeinen, M., Rahnasto, M., Wittekindt, C., Poso, A., Pelkonen, O., Raunio, H., and Juvonen, R. O. 2007. New potent and selective cytochrome P450 2B6 (CYP2B6) inhibitors based on three-dimensional quantitative structure–activity relationship (3D-QSAR) analysis. Br. J. Pharmacol. 150:932–42.

    Article  PubMed  CAS  Google Scholar 

  • Korzekwa, K. R., Jones, J. P., and Gillette, J. R. 1990. Theoretical studies on cytochrome P-450 mediated hydroxylation: A predictive model for hydrogen atom abstractions. J. Am. Chem. Soc. 112:7042–7046.

    Article  CAS  Google Scholar 

  • Krayenbuhl, J. C., Vozeh, S., Kondo-Oestreicher, M., and Dayer, P. 1999. Drug–drug interactions of new active substances: mibefradil example. Eur. J. Clin. Pharmacol. 55:559–565.

    Article  PubMed  CAS  Google Scholar 

  • Kumar, V., Wahlstrom, J. L., Rock, D. A., Warren, C. J., Gorman, L. A., and Tracy, T. S. 2006. CYP2C9 inhibition: impact of probe selection and pharmacogenetics on in vitro inhibition profiles. Drug Metab. Dispos. 34:1966–1975.

    Article  PubMed  CAS  Google Scholar 

  • Lazarou, J., Pomeranz, B. H., and Corey, P. N. 1998. Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies. JAMA 279:1200–1205.

    Article  PubMed  CAS  Google Scholar 

  • Lehmann Brothers, R. 2001. The Fruits of Genomics. p. 26.

    Google Scholar 

  • Li, Q. S., Ogawa, J., Schmid, R. D., and Shimizu, S. 2005. Indole hydroxylation by bacterial cytochrome P450 BM-3 and modulation of activity by cumene hydroperoxide. Biosci. Biotechnol. Biochem. 69:293–300.

    Article  PubMed  CAS  Google Scholar 

  • Li, A. P., and Jurima-Romet, M. 1997. Overview: pharmacokinetic drug–drug interactions. Adv. Pharmacol. 43:1–6.

    Article  PubMed  CAS  Google Scholar 

  • Locuson, C. W., Gannett, P. M., Ayscue, R., and Tracy, T. S. 2007. Use of simple docking methods to screen a virtual library for heteroactivators of cytochrome P450 2C9. J. Med. Chem. 50:1158–65.

    Article  PubMed  CAS  Google Scholar 

  • Lopez-Rangel, E., and Van Allen, M. I. 2005. Prenatal exposure to fluconazole: an identifiable dysmorphic phenotype. Birth Defects Res. A Clin. Mol. Teratol. 73:919–23.

    Article  CAS  Google Scholar 

  • Macdonald, T. L., Gutheim, W. G., Martin, R. B., and Guengerich, F. P. 1989. Oxidation of substituted N,N-dimethylanilines by cytochrome P-450: estimation of the effective oxidation–reduction potential of cytochrome P-450. Bio-chemistry 28:2071–2077.

    Article  PubMed  CAS  Google Scholar 

  • Manchester, J. I., Dinnocenzo, J. P., Higgins, L. A., and Jones, J. P. 1997. A new mechanistic probe for cytochrome P450 – an application of isotope effect profiles. J. Am. Chem. Soc. 119:5069–5070.

    Article  CAS  Google Scholar 

  • Mao, B., Gozalbes, R., Barbosa, F., Migeon, J., Merrick, S., Kamm, K., Wong, E., Costales, C., Shi, W., Wu, C., and Froloff, N. 2006. QSAR modeling of in vitro inhibition of cytochrome P450 3A4. J. Chem. Inf. Model. 46:2125–2134.

    Article  PubMed  CAS  Google Scholar 

  • Milne, G. 2000. New Drug Development in U.S. Pfizer J.

    Google Scholar 

  • Mitchell, J. R., Thorgeirsson, S. S., Potter, W. Z., Jollow, D. J., and Keiser H. 1974. Acetaminophen-induced hepatic injury: protective role of glutathione in man and rationale for therapy. Clin. Pharmacol. Ther. 16:676–684.

    PubMed  CAS  Google Scholar 

  • Miwa, G. T., Walsh, J. S., and Lu, A. Y. 1984. Kinetic isotope effects on cytochrome P450-catalyzed reactions: the oxidative O-dealkylation of 7-ethoxycoumarin. J. Biol. Chem. 259:3000–3004.

    PubMed  CAS  Google Scholar 

  • Miwa, G. T., and Lu, A. Y. H. 1987. Kinetic isotope effects and ‘metabolic switching’ in cytochrome P450-catalyzed reactions. BioEssays 7:215–219.

    Article  PubMed  CAS  Google Scholar 

  • Nelson, D. R., Koymans, L., Kamataki, T., Stegeman, J. J., Feyereisen, R., Waxman, D. J., Waterman, M. R., Gotoh, O., Coon, M. J., Estabrook, R. W., Gunsalus, I. C., and Nebert, D. W. 1996. P450 superfamily: update on new sequences, gene mapping, accession numbers and nomenclature. Pharmacogenetics 6:1–42.

    Article  PubMed  CAS  Google Scholar 

  • Newcomb, M., Hollenberg, P. F., and Coon, M. J. 2003. Multiple mechanisms and multiple oxidants in P450-catalyzed hydroxylations. Arch. Biochem. Biophys. 409:72–79.

    Article  PubMed  CAS  Google Scholar 

  • Obach, R. S. 2004. Potent inhibition of human liver aldehyde oxidase by raloxifene. Drug Metab. Dispos. 32:89–97.

    Article  PubMed  CAS  Google Scholar 

  • Obach, R. S., Huynh, P., Allen, M. C., and Beedham, C. 2004. Human liver aldehyde oxidase: inhibition by 239 drugs. J. Clin. Pharmacol. 44:7–19.

    Article  PubMed  CAS  Google Scholar 

  • Obach, R. S., and Walsky, R. L. 2005. Drugs that inhibit oxidation reactions catalyzed by aldehyde oxidase do not inhibit the reductive metabolism of ziprasidone to its major metabolite, S-methyldihydroziprasidone: an in vitro study. J. Clin. Psychopharmacol. 25:605–608.

    Article  PubMed  CAS  Google Scholar 

  • O'Brien, S. E., and de Groot, M. J. 2005. Greater than the sum of its parts: combining models for useful ADMET prediction. J. Med. Chem. 48:1287–91.

    Article  PubMed  Google Scholar 

  • Ogliaro, F., de Visser, S. P., Cohen, S., Sharma, P. K., and Shaik, S. 2002. Searching for the second oxidant in the catalytic cycle of cytochrome P450: a theoretical investigation of the iron(III)-hydroperoxo species and its epoxidation pathways. J. Am. Chem. Soc. 124:2806–2817.

    Article  PubMed  CAS  Google Scholar 

  • Olsen, L., Rydberg, P., Rod, T. H., and Ryde, U. 2006. Prediction of activation energies for hydrogen abstraction by cytochrome P450. J. Med. Chem. 49:6489–6499.

    Article  PubMed  CAS  Google Scholar 

  • Ortiz de Montellano, P. R. 1995. Cytochrome P450:Structure, Mechanism, and Biochemistry. New York: Plenum.

    Google Scholar 

  • Park, K., Williams, D. P., Naisbitt, D. J., Kitteringham, N. R., and Pirmohamed, M. 2005. Investigation of toxic metabolites during drug development. Toxicol. Appl. Pharmacol. 207(2 Suppl):425–434.

    Article  PubMed  Google Scholar 

  • Porter, W. R., Branchflower, R. V., and Trager, W. F. 1977. A kinetic method for the determination of multiple forms of microsomal cytochrome P-450. Biochem. Pharmacol. 26:549–550.

    Article  PubMed  CAS  Google Scholar 

  • Prentis, R. A., Lis, Y., and Walker, S. R. 1988. Pharmaceutical innovation by the seven UK-owned pharmaceutical companies (1964–1985). Br. J. Clin. Pharmacol. 25:387–396.

    PubMed  CAS  Google Scholar 

  • Prueksaritanont, T., Gorham, L. M., Ma, B., Liu, L., Yu, X., Zhao, J. J., Slaughter, D. E., Arison, B. H., and Vyas, K. P. 1997. In vitro metabolism of simvastatin in humans [SBT]identification of metabolizing enzymes and effect of the drug on hepatic P450s. Drug Metab. Dispos. 25:1191–1199.

    PubMed  CAS  Google Scholar 

  • Rao, S., Aoyama, R., Schrag, M., Trager, W. F., Rettie, A., and Jones, J. P. 2000. A refined 3-dimensional QSAR of cytochrome P450 2C9: computational predictions of drug interactions. J. Med. Chem. 43:2789–2796.

    Article  PubMed  CAS  Google Scholar 

  • Rettie, A. E., and Jones, J. P. 2005. Clinical and toxicological relevance of CYP2C9: Drug–drug interactions and pharmacogenetics. Ann. Rev. Pharmacol. Toxicol. 45:477–494.

    Article  CAS  Google Scholar 

  • Seeman, J. I. 1983. Effect of conformational changes on reactivity in organic chemistry. Evaluations, applications, and extensions of Curtin–Hammett/Winstein–Holness kinetics. Chem. Rev. 83:83–134.

    Article  CAS  Google Scholar 

  • Shaik, S., Kumar, D., de Visser, S. P., Altun, A., and Thiel, W. 2005. Theoretical perspective on the structure and mechanism of cytochrome P450 enzymes. Chem. Rev. 105: 2279–2328.

    Article  PubMed  CAS  Google Scholar 

  • Sharma, P. K., De Visser, S. P., and Shaik, S. 2003. Can a single oxidant with two spin states masquerade as two different oxidants? A study of the sulfoxidation mechanism by cytochrome p450. J. Am. Chem. Soc. 125:8698–8699.

    Article  PubMed  CAS  Google Scholar 

  • Sharma, U., Roberts, E. S., and Hollenberg, P. F. 1996. Formation of a metabolic intermediate complex of cytochrome P4502B1 by clorgyline. Drug Metab. Dispos. 24:1247–1253.

    PubMed  CAS  Google Scholar 

  • Singh, S. B., Shen, L. Q., Walker, M. J., and Sheridan, R. P. 2003. A model for predicting likely sites of CYP3A4-mediated metabolism on drug-like molecules. J. Med. Chem. 46:1330–1336.

    Article  PubMed  CAS  Google Scholar 

  • Sorich, M. J., Miners, J. O., McKinnon, R. A., Winkler, D. A., Burden, F. R., and Smith. P. A. 2003. Comparison of linear and nonlinear classification algorithms for the prediction of drug and chemical metabolism by human UDP-glucuronosyltransferase isoforms. J. Chem. Inf. Comput. Sci. 43:2019–2024.

    Article  PubMed  CAS  Google Scholar 

  • Streeter, A. J., Dahlin, D. C., Nelson, S. D., and Baillie, T. A. 1984. The covalent binding of acetaminophen to protein. Evidence for cysteine residues as major sites of arylation in vitro. Chem. Biol. Interact. 48:349–66.

    Article  PubMed  CAS  Google Scholar 

  • Tornero-Velez, R., Ross, M. K., Granville, C., Laskey, J., Jones, J. P., DeMarini, D. M., and Evans, M. V. 2004. Metabolism and mutagenicity of source water contaminants 1,3-dichloropropane and 2,2-dichloropropane. Drug Metab. Dispos. 32:123–131.

    Article  PubMed  CAS  Google Scholar 

  • Vatsis, K. P., and Coon, M. J. 2002. Ipso-substitution by cytochrome P450 with conversion of p-hydroxybenzene derivatives to hydroquinone: evidence for hydroperoxo-iron as the active oxygen species. Arch. Biochem. Biophys. 397:119–129.

    Article  PubMed  CAS  Google Scholar 

  • Vaz, A. D., Pernecky, S. J., Raner, G. M., and Coon, M. J. 1996. Peroxo-iron and oxenoid-iron species as alternative oxygenating agents in cytochrome P450-catalyzed reactions: switching by threonine-302 to alanine mutagenesis of cytochrome P450 2B4. Proc. Natl. Acad. Sci. USA 93:4644–4648.

    Google Scholar 

  • Vaz, A. D., and Coon, M. J. 1987. Hydrocarbon formation in the reductive cleavage of hydroperoxides by cytochrome P-450. Proc. Natl. Acad. Sci. USA 84:1172–1176.

    Google Scholar 

  • Vaz, A. D. N., McGinnity, D. F., and Coon, M. J. 1998. Epoxidation of olefins by cytochrome P450: Evidence from site-specific mutagenesis for hydroperoxo-iron as an electrophilic oxidant. Proc. Natl. Acad. Sci. USA 95:3555–3560.

    Google Scholar 

  • Vaz, A. D., Roberts, E. S., and Coon, M. J. 1990. Reductive beta-scission of the hydroperoxides of fatty acids and xenobiotics: role of alcohol-inducible cytochrome P-450. Proc. Natl. Acad. Sci. USA 87:5499–5503.

    Google Scholar 

  • Volz, T. J., Rock, D. A., and Jones, J. P. 2002. Evidence for two different active oxygen species in cytochrome p450 BM3 mediated sulfoxidation and N-dealkylation reactions. J. Am. Chem. Soc. 124:9724–9725.

    Article  PubMed  CAS  Google Scholar 

  • Watanabe, Y. 2001. Alternatives to the oxoferryl porphyrin cation radical as the proposed reactive intermediate of cytochrome P450: two-electron oxidized Fe(III) porphyrin derivatives. J. Biol. Inorg. Chem. 6:846–856.

    Article  PubMed  CAS  Google Scholar 

  • Yamashita, F., Fujiwara, S., Wanchana, S., and Hashida, M. 2006. Quantitative structure/activity relationship modelling of pharmacokinetic properties using genetic algorithm-combined partial least squares method. J. Drug Target. 14:496–504.

    Article  PubMed  CAS  Google Scholar 

  • Yin, H., Anders, M. W., Korzekwa, K. R., Higgins, L., Thummel, K. E., Kharasch, E. D., and Jones, J. P. 1995. Designing safer chemicals: predicting the rates of metabolism of halogenated alkanes. Proc. Nat. Acad. Sci. USA 92:11076–11080.

    Google Scholar 

  • Yin, H. Q., Anders, M. W., and Jones, J. P. 1996. Metabolism Of 1,2-dichloro-1-fluoroethane and 1-fluoro-1,2,2-trichloroethane – electronic factors govern the regioselectivity of cytochrome P450-dependent oxidation. Chem. Res. Toxicol. 9:50–57.

    Article  PubMed  CAS  Google Scholar 

  • Yin, H. Q., Jones, J. P., and Anders, M. W. 1995. Metabolism of 1-fluoro-1,1,2-trichloroethane, 1,2-dichloro-1,1-difluoroethane, and 1,1,1-trifluoro-2-chloroethane. Chem. Res. Toxicol. 8:262–268.

    Article  PubMed  CAS  Google Scholar 

  • Zamora, I., Afzelius, L., and Cruciani, G. 2003. Predicting drug metabolism: A site of metabolism prediction tool applied to the cytochrome P4502C9. J. Med. Chem. 46:2313–2324.

    Article  PubMed  CAS  Google Scholar 

  • Zhou, D. S., Afzelius, L., Grimm, S. W., Andersson, T. B., Zauhar, R. J., and Zamora, I. 2006. Comparison of methods for the prediction of the metabolic sites for CYP3A4-mediated metabolic reactions. Drug Metab. Dispos. 34: 976–983.

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported in part by ES009122 and GM 32165.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Jeffrey P. Jones .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2008 Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Jones, J.P. (2008). Metabolic Concerns in Drug Design. In: Elfarra, A. (eds) Advances in Bioactivation Research. Biotechnology: Pharmaceutical Aspects, vol IX. Springer, New York, NY. https://doi.org/10.1007/978-0-387-77300-1_1

Download citation

Publish with us

Policies and ethics