673
Views
61
CrossRef citations to date
0
Altmetric
Review

Chemical toxicology: reactive intermediates and their role in pharmacology and toxicology

Pages 923-946 | Published online: 24 Nov 2006

Bibliography

  • CALDWELL GW, RITCHIE DM, MASUCCI JA, HAGEMAN W, YAN Z: The new pre-preclinical paradigm: compound optimization in early and late phase drug discovery. Curr. Top. Med. Chem. (2001) 1(5):353-366.
  • DIMASI JA: Risks in new drug development: approval success rates for investigational drugs. Clin. Pharmacol. Ther. (2001) 69(5):297-307.
  • UETRECHT J: Prediction of a new drug’s potential to cause idiosyncratic reactions. Curr. Opin. Drug Discov. Devel. (2001) 4(1):55-59.
  • WILLIAMS DP, NAISBITT DJ: Toxicophores: groups and metabolic routes associated with increased safety risk. Curr. Opin. Drug Discov. Devel. (2002) 5(1):104-115.
  • JU C, UETRECHT JP: Mechanism of idiosyncratic drug reactions: reactive metabolite formation, protein binding and the regulation of the immune system. Curr. Drug Metab. (2002) 3(4):367-377.
  • KALGUTKAR AS, GARDNER I, OBACH RS et al.: A comprehensive listing of bioactivation pathways of organic functional groups. Curr. Drug Metab. (2005) 6(3):161-225.
  • NELSON SD, PEARSON PG: Covalent and noncovalent interactions in acute lethal cell injury caused by chemicals. Ann. Rev. Pharmacol. Toxicol. (1990) 30:169-195.
  • MILLER EC, MILLER JA: Mechanisms of chemical carcinogenesis: nature of proximate carcinogens and interactions with macromolecules. Pharmacol. Rev. (1966) 18(1):805-838.
  • MILLER JA: Carcinogenesis by chemicals: an overview – G. H. A. Clowes memorial lecture. Cancer Res. (1970) 30(3):559-576.
  • GILLETTE JR, MITCHELL JR, BRODIE BB: Biochemical mechanisms of drug toxicity. Ann. Rev. Pharmacol. (1974) 14:271-289.
  • JOLLOW DJ, MITCHELL JR, POTTER WZ et al.: Acetaminophen-induced hepatic necrosis. II. Role of covalent binding in vivo. J. Pharmacol. Exp. Ther. (1973) 187(1):195-202.
  • KALGUTKAR AS, DALVIE DK, O’DONNELL JP, TAYLOR TJ, SAHAKIAN DC: On the diversity of oxidative bioactivation reactions on nitrogen-containing xenobiotics. Curr. Drug Metab. (2002) 3(4):379-424.
  • NELSON SD: Structure–toxicity relationships – how useful are they in predicting toxicities of new drugs? Adv. Exp. Med. Biol. (2001) 500:33-43.
  • GILLETTE JR: Overview of drug–protein binding. Ann. NY Acad. Sci. (1973) 226:6-17.
  • PUMFORD NR, HALMES NC: Protein targets of xenobiotic reactive intermediates. Ann. Rev. Pharmacol. Toxicol. (1997) 37:91-117.
  • PARK BK, KITTERINGHAM NR, MAGGS JL, PIRMOHAMED M, WILLIAMS DP: The role of metabolic activation in drug-induced hepatotoxicity. Ann. Rev. Pharmacol. Toxicol. (2005) 45:177-202.
  • GILLETTE JR, POHL LR: A prospective on covalent binding and toxicity. J. Toxicol. Environ. Health. (1977) 2(4):849-871.
  • GILLETTE JR: Commentary. A perspective on the role of chemically reactive metabolites of foreign compounds in toxicity. I. Correlation of changes in covalent binding of reactivity metabolites with changes in the incidence and severity of toxicity. Biochem. Pharmacol. (1974) 23(20):2785-2794.
  • RASHED MS, STREETER AJ, NELSON SD: Investigations of the N-hydroxylation of 3′-hydroxyacetanilide, a non-hepatotoxic positional isomer of acetaminophen. Drug Metab. Dispos. (1989) 17(4):355-359.
  • KOEN YM, HANZLIK RP: Identification of seven proteins in the endoplasmic reticulum as targets for reactive metabolites of bromobenzene. Chem. Res. Toxicol. (2002) 15(5):699-706.
  • FREY N, CHRISTEN U, JENO P et al.: The lipoic acid containing components of the 2-oxoacid dehydrogenase complexes mimic trifluoroacetylated proteins and are autoantigens associated with halothane hepatitis. Chem. Res. Toxicol. (1995) 8(5):736-746.
  • QIU Y, BENET LZ, BURLINGAME AL: Identification of the hepatic protein targets of reactive metabolites of acetaminophen in vivo in mice using two-dimensional gel electrophoresis and mass spectrometry. J. Biol. Chem. (1998) 273(28):17940-17953.
  • JONES JA, KAPHALIA L, TREINEN-MOSLEN M, LIEBLER DC: Proteomic characterization of metabolites, protein adducts and biliary proteins in rats exposed to 1,1-dichloroethylene or diclofenac. Chem. Res. Toxicol. (2003) 16:1306-1317.
  • LANDSTEINER K, JACOBY J: Studies on the sensitization of animals with simple chemical compounds. J. Exp. Med. (1935) 61:643-656.
  • PICHLER WJ: Pharmacological interaction of drugs with antigen-specific immune receptors: the p-i concept. Curr. Opin. Allergy Clin. Immunol. (2002) 2(4):301-305.
  • LINDBERG P, NORDBERG P, ALMINGER T, BRANDSTROM A, WALLMARK B: The mechanism of action of the gastric acid secretion inhibitor omeprazole. J. Med. Chem. (1986) 29(8):1327-1329.
  • OLBE L, CARLSSON E, LINDBERG P: A proton-pump inhibitor expedition: the case histories of omeprazole and esomeprazole. Nat. Rev. Drug Discov. (2003) 2(2):132-139.
  • FELLENIUS E, BERGLINDH T, SACHS G et al.: Substituted benzimidazoles inhibit gastric acid secretion by blocking (H+ + K+) ATPase. Nature (1981) 290(5802):159-161.
  • JACKSON J, MILLER WR, DIXON JM: Safety issues surrounding the use of aromatase inhibitors in breast cancer. Expert Opin. Drug Saf. (2003) 2(1):73-86.
  • BRUEGGEMEIER RW: Aromatase inhibitors in breast cancer therapy. Expert Rev. Anti-Cancer Ther. (2002) 2(2):181-191.
  • DI SALLE E, BRIATICO G, GIUDICI D et al.: Novel aromatase and 5α-reductase inhibitors. J. Steroid Biochem. Mol. Biol. (1994) 49(4-6):289-294.
  • LOMBARDI P: Exemestane, a new steroidal aromatase inhibitor of clinical relevance. Biochim. Biophys. Acta (2002) 1587(2-3):326-337.
  • MILLER WR, JACKSON J: The therapeutic potential of aromatase inhibitors. Expert Opin. Investig. Drugs (2003) 12(3):337-351.
  • OHBAYASHI H: Neutrophil elastase inhibitors as treatment for COPD. Expert Opin. Investig. Drugs (2002) 11(7):965-980.
  • MALHOTRA S, MAN SF, SIN DD: Emerging drugs for the treatment of chronic obstructive pulmonary disease. Expert Opin. Emerging Drugs (2006) 11(2):275-291.
  • MACDONALD SJ, DOWLE MD, HARRISON LA et al.: The discovery of a potent, intracellular, orally bioavailable, long duration inhibitor of human neutrophil elastase – GW311616A a development candidate. Bioorg. Med. Chem. Lett. (2001) 11(7):895-898.
  • MACDONALD SJ, DOWLE MD, HARRISON LA et al.: Intracellular inhibition of human neutrophil elastase by orally active pyrrolidine-trans-lactams. Bioorg. Med. Chem. Lett. (2001) 11(2):243-246. [erratum appears in Bioorg. Med. Chem. Lett. (2001) 11(9):1249]
  • MACDONALD SJ, DOWLE MD, HARRISON LA et al.: Discovery of further pyrrolidine trans-lactams as inhibitors of human neutrophil elastase (HNE) with potential as development candidates and the crystal structure of HNE complexed with an inhibitor (GW-475151). J. Med. Chem. (2002) 45(18):3878-3890.
  • KENNA JG, JONES RM: The organ toxicity of inhaled anesthetics. Anesth. Analg. (1995) 81(6 Suppl.):S51-S66.
  • GUT J, CHRISTEN U, HUWYLER J: Mechanisms of halothane toxicity: novel insights. Pharmacol. Ther. (1993) 58(2):133-155.
  • ELIASSON E, KENNA JG: Cytochrome P450 2E1 is a cell surface autoantigen in halothane hepatitis. Mol. Pharmacol. (1996) 50(3):573-582.
  • CAMPAGNA JA, MILLER KW, FORMAN SA: Mechanisms of actions of inhaled anesthetics. N. Engl. J. Med. (2003) 348(21):2110-2124.
  • WIKLUND RA, ROSENBAUM SH: Anesthesiology – first of two parts. N. Engl. J. Med. (1997) 337(16):1132-1141.
  • CARRIGAN TW, STRAUGHEN WJ: A report of hepatic necrosis and death following isoflurane anesthesia. Anesthesiology (1987) 67(4):581-583.
  • MARTIN JL, PLEVAK DJ, FLANNERY KD et al.: Hepatotoxicity after desflurane anesthesia. Anesthesiology (1995) 83(5):1125-1129.
  • SYMEONIDIS A, KOURAKLIS-SYMEONIDIS A, SEIMENI U et al.: Ticlopidine-induced aplastic anemia: two new case reports, review, and meta-analysis of 55 additional cases. Am. J. Hematol. (2002) 71(1):24-32.
  • RUBIN RL, KRETZ-ROMMEL A: Phagocyte-mediated oxidation in idiosyncratic adverse drug reactions. Curr. Opin. Hematol. (2001) 8(1):34-40.
  • HA-DUONG NT, DIJOLS S, MACHEREY AC et al.: Ticlopidine as a selective mechanism-based inhibitor of human cytochrome P450 2C19. Biochemistry (2001) 40(40):12112-12122.
  • RICHTER T, MURDTER TE, HEINKELE G et al.: Potent mechanism-based inhibition of human CYP2B6 by clopidogrel and ticlopidine. J. Pharmacol. Exp. Ther. (2004) 308(1):189-197.
  • LIU ZC, UETRECHT JP: Metabolism of ticlopidine by activated neutrophils: implications for ticlopidine-induced agranulocytosis. Drug Metab. Dispos. (2000) 28(7):726-730.
  • SAVI P, PEREILLO JM, UZABIAGA MF et al.: Identification and biological activity of the active metabolite of clopidogrel. Thromb. Haemost. (2000) 84(5):891-896.
  • ZAKARIJA A, BANDARENKO N, PANDEY DK et al.: Clopidogrel-associated TTP: an update of pharmacovigilance efforts conducted by independent researchers, pharmaceutical suppliers, and the Food and Drug Administration. Stroke (2004) 35(2):533-537.
  • BENNETT CL, CONNORS JM, CARWILE JM et al.: Thrombotic thrombocytopenic purpura associated with clopidogrel. N. Engl. J. Med. (2000) 342(24):1773-1777.
  • SVENSSON CK, COWEN EW, GASPARI AA: Cutaneous drug reactions. Pharmacol. Rev. (2001) 53(3):357-379.
  • REILLY TP, JU C: Mechanistic perspectives on sulfonamide-induced cutaneous drug reactions. Curr. Opin. Allergy Clin. Immunol. (2002) 2(4):307-315.
  • CRIBB AE, MILLER M, TESORO A, SPIELBERG SP: Peroxidase-dependent oxidation of sulfonamides by monocytes and neutrophils from humans and dogs. Mol. Pharmacol. (1990) 38(5):744-751.
  • NAISBITT DJ, FARRELL J, GORDON SF et al.: Covalent binding of the nitroso metabolite of sulfamethoxazole leads to toxicity and major histocompatibility complex-restricted antigen presentation. Mol. Pharmacol. (2002) 62(3):628-637.
  • CRIBB AE, MILLER M, LEEDER JS, HILL J, SPIELBERG SP: Reactions of the nitroso and hydroxylamine metabolites of sulfamethoxazole with reduced glutathione. Implications for idiosyncratic toxicity. Drug Metab. Dispos. (1991) 19(5):900-906.
  • BARON JM, MERK HF: Drug metabolism in the skin. Curr. Opin. Allergy Clin. Immunol. (2001) 1(4):287-291.
  • REILLY TP, LASH LH, DOLL MA et al.: A role for bioactivation and covalent binding within epidermal keratinocytes in sulfonamide-induced cutaneous drug reactions. J. Investig. Dermatol. (2000) 114(6):1164-1173.
  • GILL HJ, HOUGH SJ, NAISBITT DJ et al.: The relationship between the disposition and immunogenicity of sulfamethoxazole in the rat. J. Pharmacol. Exp. Ther. (1997) 282(2):795-801.
  • NAISBITT DJ, GORDON SF, PIRMOHAMED M et al.: Antigenicity and immunogenicity of sulphamethoxazole: demonstration of metabolism-dependent haptenation and T-cell proliferation in vivo. Br. J. Pharmacol. (2001) 133(2):295-305.
  • SVENSSON CK: Do arylhydroxylamine metabolites mediate idiosyncratic reactions associated with sulfonamides? Chem. Res. Toxicol. (2003) 16(9):1035-1043.
  • MORKUNAS AR, MILLER MB: Anticonvulsant hypersensitivity syndrome. Crit. Care Clin. (1997) 13(4):727-739.
  • SCHLIENGER RG, SHEAR NH: Antiepileptic drug hypersensitivity syndrome. Epilepsia (1998) 39(Suppl. 7):S3-S7.
  • LERTRATANANGKOON K, HORNING MG: Metabolism of carbamazepine. Drug Metab. Dispos. (1982) 10(1):1-10.
  • BERTILSSON L, TOMSON T: Clinical pharmacokinetics and pharmacological effects of carbamazepine and carbamazepine-10,11-epoxide. An update. Clin. Pharmacokinet. (1986) 11(3):177-198.
  • MADDEN S, MAGGS JL, PARK BK: Bioactivation of carbamazepine in the rat in vivo. Evidence for the formation of reactive arene oxide(s). Drug Metab. Dispos. (1996) 24(4):469-479.
  • LILLIBRIDGE JH, AMORE BM, SLATTERY JT et al.: Protein-reactive metabolites of carbamazepine in mouse liver microsomes. Drug Metab. Dispos. (1996) 24(5):509-514.
  • PIRMOHAMED M, KITTERINGHAM NR, GUENTHNER TM, BRECKENRIDGE AM, PARK BK: An investigation of the formation of cytotoxic, protein-reactive and stable metabolites from carbamazepine in vitro. Biochem. Pharmacol. (1992) 43(8):1675-1682.
  • PEARCE RE, VAKKALAGADDA GR, LEEDER JS: Pathways of carbamazepine bioactivation in vitro I. Characterization of human cytochromes P450 responsible for the formation of 2- and 3-hydroxylated metabolites. Drug Metab. Dispos. (2002) 30(11):1170-1179.
  • MAGGS JL, PIRMOHAMED M, KITTERINGHAM NR, PARK BK: Characterization of the metabolites of carbamazepine in patient urine by liquid chromatography/mass spectrometry. Drug Metab. Dispos. (1997) 25(3):275-280.
  • FURST SM, SUKHAI P, MCCLELLAND RA, UETRECHT JP: Covalent binding of carbamazepine oxidative metabolites to neutrophils. Drug Metab. Dispos. (1995) 23(5):590-594.
  • FURST SM, UETRECHT JP: The effect of carbamazepine and its reactive metabolite, 9-acridine carboxaldehyde, on immune cell function in vitro. Int. J. Immunopharmacol. (1995) 17(5):445-452.
  • PEARCE RE, UETRECHT JP, LEEDER JS: Pathways of carbamazepine bioactivation in vitro: II. The role of human cytochrome P450 enzymes in the formation of 2-hydroxyiminostilbene. Drug Metab. Dispos. (2005) 33(12):1819-1826.
  • JU C, UETRECHT JP: Detection of 2-hydroxyiminostilbene in the urine of patients taking carbamazepine and its oxidation to a reactive iminoquinone intermediate. J. Pharmacol. Exp. Ther. (1999) 288(1):51-56.
  • WOLKENSTEIN P, TAN C, LECOEUR S et al.: Covalent binding of carbamazepine reactive metabolites to P450 isoforms present in the skin. Chem. Biol. Interact. (1998) 113(1):39-50.
  • DIECKHAUS CM, THOMPSON CD, ROLLER SG, MACDONALD TL: Mechanisms of idiosyncratic drug reactions: the case of felbamate. Chem. Biol. Interact. (2002) 142(1-2):99-117.
  • THOMPSON CD, KINTER MT, MACDONALD TL: Synthesis and in vitro reactivity of 3-carbamoyl-2-phenylpropionaldehyde and 2-phenylpropenal: putative reactive metabolites of felbamate. Chem. Res. Toxicol. (1996) 9(8):1225-1229.
  • KAPETANOVIC IM, TORCHIN CD, STRONG JM et al.: Reactivity of atropaldehyde, a felbamate metabolite in human liver tissue in vitro. Chem. Biol. Interact. (2002) 142(1-2):119-134.
  • POPOVIC M, NIERKENS S, PIETERS R, UETRECHT J: Investigating the role of 2-phenylpropenal in felbamate-induced idiosyncratic drug reactions. Chem. Res. Toxicol. (2004) 17(12):1568-1576.
  • GERBER N, DICKINSON RG, HARLAND RC et al.: Reye-like syndrome associated with valproic acid therapy. J. Pediatr. (1979) 95(1):142-144.
  • BAILLIE TA: Metabolic activation of valproic acid and drug-mediated hepatotoxicity. Role of the terminal olefin, 2-n-propyl-4-pentenoic acid. Chem. Res. Toxicol. (1988) 1(4):195-199.
  • RETTENMEIER AW, PRICKETT KS, GORDON WP et al.: Studies on the biotransformation in the perfused rat liver of 2-n-propyl-4-pentenoic acid, a metabolite of the antiepileptic drug valproic acid. Evidence for the formation of chemically reactive intermediates. Drug Metab. Dispos. (1985) 13(1):81-96.
  • FROMENTY B, PESSAYRE D: Inhibition of mitochondrial β-oxidation as a mechanism of hepatotoxicity. Pharmacol. Ther. (1995) 67(1):101-154.
  • TANG W, PALATY J, ABBOTT FS: Time course of α-fluorinated valproic acid in mouse brain and serum and its effect on synaptosomal gamma-aminobutyric acid levels in comparison to valproic acid. J. Pharmacol. Exp. Ther. (1997) 282(3):1163-1172.
  • TANG W, BOREL AG, FUJIMIYA T, ABBOTT FS: Fluorinated analogues as mechanistic probes in valproic acid hepatotoxicity: hepatic microvesicular steatosis and glutathione status. Chem. Res. Toxicol. (1995) 8(5):671-682.
  • GRILLO MP, CHIELLINI G, TONELLI M, BENET LZ: Effect of α-fluorination of valproic acid on valproyl-S-acyl-CoA formation in vivo in rats. Drug Metab. Dispos. (2001) 29(9):1210-1215.
  • CANNELL GR, BAILEY MJ, DICKINSON RG: Inhibition of tubulin assembly and covalent binding to microtubular protein by valproic acid glucuronide in vitro. Life Sci. (2002) 71(22):2633-2643.
  • DE PAULIS T: ONO-2506. Ono. Curr. Opin. Investig. Drugs (2003) 4(7):863-867.
  • TATEISHI N, MORI T, KAGAMIISHI Y et al.: Astrocytic activation and delayed infarct expansion after permanent focal ischemia in rats. Part II: suppression of astrocytic activation by a novel agent (R)-(-)-2-propyloctanoic acid (ONO-2506) leads to mitigation of delayed infarct expansion and early improvement of neurologic deficits. J. Cereb. Blood Flow Metab. (2002) 22(6):723-734.
  • KATO H, ARAKI T, IMAI Y, TAKAHASHI A, ITOYAMA Y: Protection of dopaminergic neurons with a novel astrocyte modulating agent (R)-(-)-2-propyloctanoic acid (ONO-2506) in an MPTP-mouse model of Parkinson’s disease. J. Neurol. Sci. (2003) 208(1-2):9-15.
  • BIALER M, JOHANNESSEN SI, KUPFERBERG HJ et al.: Progress report on new antiepileptic drugs: a summary of the Seventh Eilat Conference (EILAT VII). Epilepsy Res. (2004) 61(1-3):1-48.
  • PARKER RJ, HARTMAN NR, ROECKLEIN BA et al.: Stability and comparative metabolism of selected felbamate metabolites and postulated fluorofelbamate metabolites by postmitochondrial suspensions. Chem. Res. Toxicol. (2005) 18(12):1842-1848.
  • SWIFT RM: Drug therapy for alcohol dependence. N. Engl. J. Med. (1999) 340(19):1482-1490.
  • ELIASSON E, STAL P, OKSANEN A, LYTTON S: Expression of autoantibodies to specific cytochromes P450 in a case of disulfiram hepatitis. J. Hepatol. (1998) 29(5):819-825.
  • VALLARI RC, PIETRUSZKO R: Human aldehyde dehydrogenase: mechanism of inhibition of disulfiram. Science (1982) 216(4546):637-639.
  • SHEN ML, JOHNSON KL, MAYS DC, LIPSKY JJ, NAYLOR S: Determination of in vivo adducts of disulfiram with mitochondrial aldehyde dehydrogenase. Biochem. Pharmacol. (2001) 61(5):537-545.
  • ERVE JC, JENSEN ON, VALENTINE HS, AMARNATH V, VALENTINE WM: Disulfiram generates a stable N,N-diethylcarbamoyl adduct on Cys-125 of rat hemoglobin β-chains in vivo. Chem. Res. Toxicol. (2000) 13(4):237-244.
  • TONKIN EG, ERVE JC, VALENTINE WM: Disulfiram produces a non-carbon disulfide-dependent schwannopathy in the rat. J. Neuropathol. Exp. Neurol. (2000) 59(9):786-797.
  • BESSEMS JG, VERMEULEN NP: Paracetamol (acetaminophen)-induced toxicity: molecular and biochemical mechanisms, analogues and protective approaches. Crit. Rev. Toxicol. (2001) 31(1):55-138.
  • CHEN W, KOENIGS LL, THOMPSON SJ et al.: Oxidation of acetaminophen to its toxic quinone imine and nontoxic catechol metabolites by baculovirus-expressed and purified human cytochromes P450 2E1 and 2A6. Chem. Res. Toxicol. (1998) 11(4):295-301.
  • ALBANO E, RUNDGREN M, HARVISON PJ, NELSON SD, MOLDEUS P: Mechanisms of N-acetyl-p-benzoquinone imine cytotoxicity. Mol. Pharmacol. (1985) 28(3):306-311.
  • VAN DE STRAAT R, DE VRIES J, DEBETS AJ, VERMEULEN NP: The mechanism of prevention of paracetamol-induced hepatotoxicity by 3,5-dialkyl substitution. The roles of glutathione depletion and oxidative stress. Biochem. Pharmacol. (1987) 36(13):2065-2070.
  • MATTHEWS AM, HINSON JA, ROBERTS DW, PUMFORD NR: Comparison of covalent binding of acetaminophen and the regioisomer 3′-hydroxyacetanilide to mouse liver protein. Toxicol. Lett. (1997) 90(1):77-82.
  • HALMES NC, SAMOKYSZYN VM, HINTON TW, HINSON JA, PUMFORD NR: The acetaminophen regioisomer 3′-hydroxyacetanilide inhibits and covalently binds to cytochrome P450 2E1. Toxicol. Lett. (1998) 94(1):65-71.
  • CHEN W, SHOCKCOR JP, TONGE R et al.: Protein and nonprotein cysteinyl thiol modification by N-acetyl-p-benzoquinone imine via a novel ipso adduct. Biochemistry (1999) 38(25):8159-8166.
  • KITTERINGHAM NR, LAMBERT C, MAGGS JL, COLBERT J, PARK BK: A comparative study of the formation of chemically reactive drug metabolites by human liver microsomes. Br. J. Clin. Pharmacol. (1988) 26(1):13-21.
  • QIU Y, BENET LZ, BURLINGAME AL: Identification of hepatic protein targets of the reactive metabolites of the non-hepatotoxic regioisomer of acetaminophen, 3′-hydroxyacetanilide, in the mouse in vivo using two-dimensional gel electrophoresis and mass spectrometry. Adv. Exp. Med. Biol. (2001) 500:663-673.
  • FOUNTOULAKIS M, BERNDT P, BOELSTERLI UA et al.: Two-dimensional database of mouse liver proteins: changes in hepatic protein levels following treatment with acetaminophen or its nontoxic regioisomer 3-acetamidophenol. Electrophoresis (2000) 21(11):2148-2161.
  • NADAL R: Pharmacology of the atypical antipsychotic remoxipride, a dopamine D2 receptor antagonist. CNS Drug Rev. (2001) 7(3):265-282.
  • LAIDLAW ST, SNOWDEN JA, BROWN MJ: Aplastic anaemia and remoxipride. Lancet (1993) 342(8881):1245.
  • WIDMAN M, NILSSON LB, BRYSKE B, LUNDSTROM J: Disposition of remoxipride in different species. Species differences in metabolism. Arzneimittel-Forschung (1993) 43(3):287-297.
  • INAYAT-HUSSAIN SH, MCGUINNESS SM, JOHANSSON R, LUNDSTROM J, ROSS D: Caspase-dependent and -independent mechanisms in apoptosis induced by hydroquinone and catechol metabolites of remoxipride in HL-60 cells. Chem. Biol. Interact. (2000) 128(1):51-63.
  • MCGUINNESS SM, JOHANSSON R, LUNDSTROM J, ROSS D: Induction of apoptosis by remoxipride metabolites in HL60 and CD34+/CD19- human bone marrow progenitor cells: potential relevance to remoxipride-induced aplastic anemia. Chem. Biol. Interact. (1999) 121(3):253-265.
  • ERVE JCL, SVENSSON MA, VON EULER-CHELPIN H, KLASSON-WEHLER E: Characterization of glutathione conjugates of the remoxipride hydroquinone metabolite NCQ-344 formed in vitro and detection following oxidation by human neutrophils. Chem. Res. Toxicol. (2004) 17(4):564-571.
  • DE PAULIS T: The discovery of epidepride and its analogs as high-affinity radioligands for imaging extrastriatal dopamine D(2) receptors in human brain. Curr. Pharm. Des. (2003) 9(8):673-696.
  • BORGES N: Tolcapone-related liver dysfunction: implications for use in Parkinson’s disease therapy. Drug Saf. (2003) 26(11):743-747.
  • BENABOU R, WATERS C: Hepatotoxic profile of catechol-O-methyltransferase inhibitors in Parkinson’s disease. Expert Opin. Drug Saf. (2003) 2(3):263-267.
  • JORGA K, FOTTELER B, HEIZMANN P, GASSER R: Metabolism and excretion of tolcapone, a novel inhibitor of catechol-O-methyltransferase. Br. J. Clin. Pharmacol. (1999) 48(4):513-520.
  • SMITH KS, SMITH PL, HEADY TN et al.: In vitro metabolism of tolcapone to reactive intermediates: relevance to tolcapone liver toxicity. Chem. Res. Toxicol. (2003) 16(2):123-128.
  • HAASIO K, SOPANEN L, VAALAVIRTA L, LINDEN IB, HEINONEN EH: Comparative toxicological study on the hepatic safety of entacapone and tolcapone in the rat. J. Neural Transm. (2001) 108(1):79-91.
  • NISSINEN E, KAHEINEN P, PENTTILA KE, KAIVOLA J, LINDEN IB: Entacapone, a novel catechol-O-methyltransferase inhibitor for Parkinson’s disease, does not impair mitochondrial energy production. Eur. J. Pharmacol. (1997) 340(2-3):287-294.
  • HAASIO K, KOPONEN A, PENTTILA KE, NISSINEN E: Effects of entacapone and tolcapone on mitochondrial membrane potential. Eur. J. Pharmacol. (2002) 453(1):21-26.
  • LEARMONTH DA, VIEIRA-COELHO MA, BENES J et al.: Synthesis of 1-(3,4-dihydroxy-5- nitrophenyl)-2-phenyl-ethanone and derivatives as potent and long-acting peripheral inhibitors of catechol-O-methyltransferase. J. Med. Chem. (2002) 45(3):685-695.
  • SILVEIRA P, VAZ-DA-SILVA M, ALMEIDA L et al.: Pharmacokinetic–pharmacodynamic interaction between BIA 3-202, a novel COMT inhibitor, and levodopa/benserazide. Eur. J. Clin. Pharmacol. (2003) 59(8-9):603-609.
  • BREIER DV, RENDO P, GONZALEZ J et al.: Massive plasmocytosis due to methimazole-induced bone marrow toxicity. Am. J. Hematol. (2001) 67(4):259-261.
  • MIZUTANI T, YOSHIDA K, MURAKAMI M, SHIRAI M, KAWAZOE S: Evidence for the involvement of N-methylthiourea, a ring cleavage metabolite, in the hepatotoxicity of methimazole in glutathione-depleted mice: structure–toxicity and metabolic studies. Chem. Res. Toxicol. (2000) 13(3):170-176.
  • MIZUTANI T, MURAKAMI M, SHIRAI M, TANAKA M, NAKANISHI K: Metabolism-dependent hepatotoxicity of methimazole in mice depleted of glutathione. J. Appl. Toxicol. (1999) 19(3):193-198.
  • BERGMAN U, BRITTEBO EB: Methimazole toxicity in rodents: covalent binding in the olfactory mucosa and detection of glial fibrillary acidic protein in the olfactory bulb. Toxicol. Appl. Pharmacol. (1999) 155(2):190-200.
  • BRITTEBO EB: Metabolism-dependent toxicity of methimazole in the olfactory nasal mucosa. Pharmacol. Toxicol. (1995) 76(1):76-79.
  • GENTER MB, DEAMER NJ, BLAKE BL, WESLEY DS, LEVI PE: Olfactory toxicity of methimazole: dose–response and structure–activity studies and characterization of flavin-containing monooxygenase activity in the Long-Evans rat olfactory mucosa. Toxicol. Pathol. (1995) 23(4):477-486.
  • AJ H, PR G: Metabolism-directed optimization of pharmacokinetics. Curr. Drug Disc. (2004):17-22.
  • BURGEY CS, ROBINSON KA, LYLE TA et al.: Metabolism-directed optimization of 3-aminopyrazinone acetamide thrombin inhibitors. Development of an orally bioavailable series containing P1 and P3 pyridines. J. Med. Chem. (2003) 46(4):461-473.
  • BURGEY CS, ROBINSON KA, LYLE TA et al.: Pharmacokinetic optimization of 3-amino-6-chloropyrazinone acetamide thrombin inhibitors. Implementation of P3 pyridine N-oxides to deliver an orally bioavailable series containing P1 N-benzylamides. Bioorg. Med. Chem. Lett. (2003) 13(7):1353-1357.
  • ANDREWS EG, ANTOGNOLI GW, BRESLOW R et al.: Synthesis and pharmacological profile of two novel heterocyclic chromanols, CP-80,798 and CP-85,958, as potent LTD4 receptor antagonists. Bioorg. Med. Chem. Lett. (1995) 5(13):1365-1370.
  • CHAMBERS RJ, ANTOGNOLI GW, CHENG JB et al.: Development of new chromanol antagonists of leukotriene D4. Bioorg. Med. Chem. Lett. (1998) 8(14):1791-1796.
  • CHAMBERS RJ, MARFAT A, ANTOGNOLI GW et al.: Discovery of CP-199,330 and CP-199,331: two potent and orally efficacious cysteinyl LT1 receptor antagonists devoid of liver toxicity. Bioorg. Med. Chem. Lett. (1999) 9(18):2773-2778.
  • O’BRIEN SE, BROWNE HL, BRADSHAW TD et al.: Antitumor benzothiazoles. Frontier molecular orbital analysis predicts bioactivation of 2-(4-aminophenyl)benzothiazoles to reactive intermediates by cytochrome P4501A1. Org. Biomol. Chem. (2003) 1(3):493-497.
  • TRAPANI V, PATEL V, LEONG CO et al.: DNA damage and cell cycle arrest induced by 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (5F203, NSC-703786) is attenuated in aryl hydrocarbon receptor deficient MCF-7 cells. Br. J. Cancer (2003) 88(4):599-605.
  • CHUA MS, KASHIYAMA E, BRADSHAW TD et al.: Role of Cyp1A1 in modulation of antitumor properties of the novel agent 2-(4-amino-3-methylphenyl)benzothiazole (DF-203, NSC-674495) in human breast cancer cells. Cancer Res. (2000) 60(18):5196-5203.
  • BRADSHAW TD, WESTWELL AD: The development of the antitumour benzothiazole prodrug, Phortress, as a clinical candidate. Curr. Med. Chem. (2004) 11(8):1009-1021.
  • EVANS DC, BAILLIE TA: Minimizing the potential for metabolic activation as an integral part of drug design. Curr. Opin. Drug Discov. Devel. (2005) 8(1):44-50.
  • EVANS DC, WATT AP, NICOLL-GRIFFITH DA, BAILLIE TA: Drug–protein adducts: an industry perspective on minimizing the potential for drug bioactivation in drug discovery and development. Chem. Res. Toxicol. (2004) 17(1):3-16.
  • GAN J, HARPER TW, HSUEH M-M, QU Q, HUMPHREYS WG: Dansyl glutathione as a trapping agent for the quantitative estimation and identification of reactive metabolites. Chem. Res. Toxicol. (2005) 18(5):896-903.
  • SOGLIA JR, CONTILLO LG, KALGUTKAR AS et al.: A semiquantitative method for the determination of reactive metabolite conjugate levels in vitro utilizing liquid chromatography-tandem mass spectrometry and novel quaternary ammonium glutathione analogues. Chem. Res. Toxicol. (2006) 19(3):480-490.
  • YAN Z, MAHER N, TORRES R, CALDWELL GW, HUEBERT N: Rapid detection and characterization of minor reactive metabolites using stable-isotope trapping in combination with tandem mass spectrometry. Rapid Commun. Mass Spectrom. (2005) 19(22):3322-3330.
  • KWAK EL, SORDELLA R, BELL DW et al.: Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib. Proc. Natl. Acad. Sci. USA (2005) 102(21):7665-7670.
  • RABINDRAN SK, DISCAFANI CM, ROSFJORD EC et al.: Antitumor activity of HKI-272, an orally active, irreversible inhibitor of the HER-2 tyrosine kinase. Cancer Res. (2004) 64(11):3958-3965.
  • BANERJEE R, RACHID Z, MCNAMEE J, JEAN-CLAUDE BJ: Synthesis of a prodrug designed to release multiple inhibitors of the epidermal growth factor receptor tyrosine kinase and an alkylating agent: a novel tumor targeting concept. J. Med. Chem. (2003) 46(25):5546-5551.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.