Radicals

While radicals have been widely implicated in many toxicities, the chemical details of the mechanisms associated with these toxicities are less well defined. This is complicated in part by the fact that many radical forming drugs also generate electrophiles, and due to the difficulty in studying radicals in general. Radicals contain one or more unpaired electrons, and may participate in nucleophilc or electrophilic type reactions, but these are mechanistically distinct from the electrophilic processes discussed above. Reactivity can be markedly influenced by orbital symmetry, which in turn is effected by substituents (Mile 2000). The reactions of relevance to biological systems involve: 1. Direct reaction with cellular constituents to form a covalent adduct (and a resulting more stable radical). 2. Hydrogen radical abstraction to form a radical based on an endogenous cellular constituent or 3. Direct reaction with a second unpaired electron species, most importantly, molecular oxygen, generating reactive oxygen species and oxidative stress. It is likely that this last process has the most important toxicological consequences. It should be noted that the first two processes result in the formation of new radicals which potentially could also react with oxygen, and it is perhaps for this reason that the literature frequently does not address this level of mechanistic detail when oxidative stress is observed. Some of these points, together with a discussion of pathologies believed to be associated with radical formation, have been recently reviewed (Sorg 2004).

Examples of free radicals directly forming covalent adducts with biological molecules include certain compounds noted as mechanism based inhibitors of CYP (Ortiz De Montellano 1990). Thus the free radical formed during oxidation reacts with the heme group to form a covalent bonds. The particular functionalities capable of this type of mechanism based inhibition is in part a reflection the combination of their capacity for one electron oxidation chemistry mediated by CYP, and the highly delocalized nature of the heme prosthetic group, where a more stable radical localized on the heme can be formed, (although a number of different reactions are possible). Functionalities which can cause mechanism based inactivation of CYP by this mechanism include halocarbons, hydrazines, olefins, sydnones, cylopropylamines, and some dihydropyridines and dihydro-quinolines. The cyclopropylamine group is encountered in a number of drugs, and may be bioactivated to form a distonic radical cation as shown in Figure 22. The direct relevance of cyclop ropy lamines oxidation to toxicity seems to be predominantly associated with a higher risk for drug interactions, since to date there seems to be little evidence that this property is the causative event for other forms of toxicity, idiosyncratic or otherwise.

Myeloperoxidase Adverse Drug Reactions

Distonic Radical Cation Figure 22. The oxidative metabolism of cyclopropylamines to distonic radical cations.

Radicals may react with proteins to abstract a hydrogen radical, (Sorani et al. 1994), and sulfhydryl and tyrosyl groups may be likely sites for this to occur (Ostdal et al. 1999, Kolberg et al. 2002). Subsequent molecular events associated with this reaction and their possible toxicological significance have not been significantly studied, but it seems a likely initial event which may lead to covalent adduct formation, in that reaction with a second drug radical could form a closed shell species. Thus the mechanism by which radicals may form a covalent adduct to proteins is likely to be a two step process, (in contrast to electrophiles). Perhaps for this reason covalent binding of radicals to proteins with subsequent toxico-logical significance has been significantly less well demonstrated than for electrophiles. Among the few examples are ethanol, halogenated hydrocarbons, and possibly hydrazines. a Hydroxyl ethyl radicals have been shown to be formed during microsomal incubations with ethanol, and to subsequently covalently bind to proteins. These adducts have also been shown to be immunogenic, and therefore provide an alternative mechanism from acetaldehyde covalent binding, for ethanol induced immune mediated hepatitis (Moncada et al. 1994). In addition to the oxidative pathways discussed earlier, low molecular weight halocarbons can undergo reductive metabolism to form carbon or chlorine centered radicals and these have been considered as possible alternative mediators of observed hepatotoxicity. For chloroform, the reductive pathway leading to dichloromethyl radical formation is now thought to have less toxico-logical relevance than oxidative pathways, since the former pathway requires very high concentrations and anaerobic conditions (Gemma et al. 2003). Isoniazid is a drug used to treat tuberculosis, and is associated with idiosyncratic toxicities such as Lupus. It is a hydrazine derivative, and hydrazine itself has been shown to form acetyl radicals following metabolic acetylation in perfused rat livers (Sinha 1987). Iproniazid was an MAO inhibitor used for depression and was withdrawn from the market due to hepatotoxicity. Isoniazid and iproniazid have been shown to generate free radicals in vitro (Sipe et al. 2004, Johnsson and Schultz 1994), (Figure 23). Both macromolecular binding and oxidative stress have been

Iproniazid Medicine
Figure 23. Proposed radicals produced by metabolic oxidation of Isoniazid and Iproniazid.

proposed as biological consequences (Albano and Tomassi 1987). Isoniazid acetyl radicals also appear to form covalent adducts with NAD(H), (Nguyen et al. 2001).

The reaction of radicals with oxygen to produce reactive oxygen species and their subsequent biological significance has been well reviewed (Cohen and Doherty 1987, Sorg 2004, Stoh 1995). The formation of superoxide anion and hydrogen peroxide by this process may lead to glutathione depletion and oxidation of cellular components such as lipids (oxidative stress). While any radical in principle may potentially react with molecular oxygen, compounds that can reversibly form radical anions are likely to cause greater effect, since the formation of the reduced oxygen species will be in excess of the stoichiometric

Figure 24. Redox cycling by one electron oxidation of quinones and nitro aromatics, to produce reduced, active oxygen species.
Nilutamide
Figure 25. The structures of Nilutamide and Flutamide.

amount of drug (Figure 24). From a drug development standpoint however, this is mitigated by the fact that a rather limited number of functionalities so far have been noted that are capable of redox cycling by this mechanism: quinones, nitroaromatics, some quaternary ammonium compounds and transition metal complexes. Quinone redox cycling has been most extensively studied with the anthraquinone antineoplastic agents such as Doxorubicin. Long term use of Doxorubicin is associated with cardiomyopathy due to mitochondrial toxicity, and despite continued investigations, reversible quinone reduction leading to oxidative stress remains the most likely mechanism (Wallace 2003). The reduction of aromatic nitro compounds may lead to nitrogen centered electrophiles as discussed above, but the initial one electron reduction product is the nitroradical anion which may undergo redox cycling. The antiandrogen Nilutamide is used to treat prostate cancer, is hepatotoxic, and to a lesser extent also a pulmonary toxin. This appears to be due to redox cycling (Fau et al. 1992), but the free radical can also undergo further reduction to nitroso and hydroxylamine intermediates (Berson et al. 1994). Flutamide is another nitro aromatic antiandrogen associated with hepatotoxicty, and redox cycling via nitro reduction is implicated (Nunez-Vergara et al. 2001). The structures of these drugs are shown in Figure 25.

Conclusion

Reactive intermediates may be grouped according to their reactivity patterns, and reactive metabolites with similar reaction properties may derive from quite different functional groups. Reactive metabolites may be broadly classified as either electrophiles or radicals. At present, electrophiles constitute the more important group due to the wide diversity of structures that can produce these, and are hence more likely to be encountered in drug development. However, as more work focuses on searching for radical intermediates, their implication in toxicity mechanisms is likely to increase. In all but a few cases, proposed reactive metabolites have not been proven to be the cause of the toxicities to which they are associated, and in many cases a particular compound, or even a particular functional group, is capable of forming more than one type of reactive metabolite. This makes application of this type of information to drug development problematical. Never the less, approaches have been proposed by which this type of information might be applied to minimize safety risk in drug development (Evans et al. 2004).

The emphasis on bioactivation or covalent binding frequently remains a point of contention in selecting candidates for drug development. Bioactivation must be put in context with other properties of the compound, (most particularly anticipated dose level), to gauge the level of concern, and in the future is more likely to find value in combination with other types of data. The use of genomic and proteomic information to gauge safety risk in preclinical toxicology will increase significantly in coming years (Cohen 2004, Lord 2004, Selkirk and Tennat 2003, Walgren and Thompson 2004). Thus if changes in the expression of genes associated with the processing of electrophilic metabolites or oxidative stress are observed, knowing if such mechanisms are operating for a particular compound will help significantly in interpreting these findings. Also, if such properties are identified in a lead candidate, it is only by an understanding of the underlying chemistry behind them that such properties can be rationally designed out of follow up compounds.

While risk can potentially be minimized by these approaches, managing the consequences of idiosyncratic toxicities will remain a clinical issue for the foreseeable future. Here, genomics may also have significant potential. The feasibility of identifying genetic risk factors for individuals towards a particular idiosyncratic reaction has now been demonstrated (Martin et al. 2004), and if this approach is found to be general, may have significant impact in managing these important metabolically mediated toxicities.

References

Albano E and Tomassi A. Spin Trapping of Free Radical Intermediates Produced During the Metabolism of Isoniazid and Iproniazid in Isolated Hepatocytes. Biochem Pharmacol 1987; 36(18): 2913-20

Bakke O.M. Drug Safety Discontinuations in the United Kingdom, the United States, and Spain from 1974-1993: A Regulatory Perspective. Clinical Pharmacology and Therapeutics 1995; 58(1): 108-117

Bandyopadhyay U, Biswas K, and Banerjee RK. Extrathyroidal Actions of Anithyroid Thionamides. Toxicology Letters 2002; 128: 117-127

Bartke M and Pfleiderer W. Pteridines. LXXXVII. Oxidations and Reactions of 2-and 4-Thiolumazine Derivatives. Synthesis and Properties of Pteridinesulfinates and -Sulfonates. Pteridines. 1989; 1(1): 45-56

Berson A, Wolf C, Chachaty C, Fau D, and Pessayre D. Interest of ESR in Determining the Mechanisms of Drug Toxicity: Application to the Antiandrogen Nilutamide. Journal de Chimie Physique et de Physico-Chimie Biologique 1994; 91(11/12): 1809-19

Bonierbale E, Valadon P, Pons C, Desfosses B, and Dansette PM. Opposite Behaviors of Reactive Metabolites of Tienilic acid and It's Isomer Towards Liver Proteins; Use of specific Anti-Tienilic Acid -Protein Adduct Antibodies and the Possible Relationship with different Hepatotoxic Effects of the Two Compounds.

Chem Res Toxicol 1999; 12(3):286-296

Borel AG, and Abbot FS. Characterization of Novel Isocyanate- derived Metabolites of the Formamide N-Formylamphetamine with Combined Use of Electrospray Mass spectrometry and Stable Isotope Methodology. Chem Res Toxicol 1995; 8(6): 891-9

Cao K, Stack DE, Ramaanathan R, Gross ML, Rogan EG, and Cavalieri EL. Synthesis and Structure Elucidation of Estrogen quinones conjugated with Cysteine, N-Acetylcysteine, and Glutathione. Chem Res Toxicol 1998; 11: 909-916

Chou HC, Lang NP, and Kadlubar FF. Metabolic Activation of N-Hydroxy Heterocyclic Amines by Human Sulfotransferases. Cancer Research 1995; 55(3): 525-9

Cohen SM. Risk Assessment in the Genomic Era. Toxicologic Pathology 2004; 32(Suppl. 1): 3-8

Cohen GM and Doherty MD. Free Radical Mediated Cell Toxicity by Redox Cycling Chemicals. Br J Cancer 1987; 55 (Suppl VIII): 46-52

Cooper AJL, Bruschi SA, and Anders MW. Toxic Halogenated Cysteine S-conjugates and Targeting of Mitochondrial Enzymes of Energy Metabolism.

Biochemical Pharmacology 2002; 64: 553-564

Cox PJ, Ryan DA, Holis FJ, Harris AM, Miller AK,Vousden M, and Cowley H. Absorption, Disposition and Metabolism of Rosiglitazone, a Potent Thiazolidinone Insulin Sensitizer in Humans. Drug Metab Dispos 2000; 28(7): 772-780

Dalvie DK, Kalgutkar AS, Khojasteh-Bakht SC, Obach RS, and O'Donnell JP Biotransformation Reactions of Five - Membered Aromatic Heterocyclic Rings. Chem. Res Toxicol 2002; 15(3): 269-299

Dansette PM, Thang DC, El Amiri H, and Mansuy D. Evidence for Thiophene S-oxide as a Primary Reactive Metabolite of Thoiphene in vivo: Formation of a Dihydrothiophene Sulfoxide Mercapturic Acid. Biochem Biophys Res Commun 1992; 186(3): 1624-1630

Dieckhaus CM, Miller TA, Sofia RD, and MacDonald TL. A Mechanistic Approach to Understanding Species Differences in Felbamate Bioactivation: Relevance to Drug- Induced Idiosyncratic Reactions. Drug Metab Dispos 2000; 28(7): 814-822

Evans DC, Watt AP, Nicoll-Griffith DA, and 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: 3-16

Fan PW, Gu C, Marsh SA, Stevens JC. Mechanism Based Inactivation of Cytochrome P450 2B6 by a Novel Terminal Acetylene Inhibitor. Drug Metab Dispos 2003; 31(1): 28-36

Fau D, Berson A, Eugene D, Fromenty B, Fisch C, and Pessayre D. Mechanism for the Hepatotoxicity of the Antiandrogen Nilutamide. Evidence Suggesting that Redox Cycling of this Nitroaromatic Drug Leads to Oxidative Stress in Isolated Hepatocytes. J Pharmacol. Exp Ther 1992; 263(1): 69-77

Galtier P. Biotransformation and Fate of Mycotoxins. J. Toxicology Toxin Reviews 1999; (18 3&4): 295-312

Gemma S, Vittozzi L, Testai E. Metabolism of Chloroform in the Human Liver and Identification of the Competent P450's. Drug Metab Dispos 2003; 31(3): 266-274

Gillies PS and Dunn CJ. Pioglitazone. Drugs 2000; 60(2): 333-343

Glatt H. Sulfotransferases in the Bioactivation of Xenobiotics. Chemico-Biological Interactions 2000; 129(1-2): 141-170

Goldin C, and Boelsterli UA. Dissociation of Covalent Protein Adduct Formation from Oxidative Injury in Cultured Hepatocytes Exposed to Cocaine. Xenobiotica. 1994; 24(3): 251-264

Gorrod JW and Aislaitner G. The Metabolism of Alicyclic Amines to Reactive Iminium Ion Intermediates. Eur J of Drug Metabolism and Pharmacokinetics. 1994; 19(3): 209-217

Guengerich FP and Johnson WW. Kinetics of Hydrolysis and Reaction of Aflatoxin B1 Exo-8,9-Epoxide and Relevance to Toxicity and Deactivation. Drug Metab Rev 1999; 31(1): 141-158

Hanzlik RP, Vyas KP, and Traiger GJ. Substituent Effects on the Hepatotoxicity of Thiobenzamide Derivatives in the Rat. Toxicol and Appl Pharmacol 1978; 46(3): 685-94.

He K, Talaat RE, Pool WF, Reily MD, Reed JE, Bridges AJ, and Woolf TF. Metabolic Activation of Troglitazone : Identification of A Reactive Metabolite and Mechanisms Involved. Drug Metab Dispos 2004; 32(6): 639-646

Hinson JA, Pumford NR, and Nelson SD. The Role of Metabolic Activation in Drug Toxicity. Drug Metab Rev. 1994; 261(1&2): 395-412

Holme JA, Dahlin DC, Nelson SD, and Dybing E. Cytotoxic Effects of N-Acetyl-p-Benzoquinone Imine, a Common Arylating Intermediate of Paracetamol and N-Hydroxyparacetamol. Biochem Pharmacol 1984; 33: 401-406

Jerina DM. From Arene Oxides to Diol Epoxides and DNA. Polycyclic Aromatic Hydrocarbons 2000; 19(1-4): 5-36

Johnston JN, Wright CL, Leeson GA. Regioselectivity of Metabolic Activation of Acetylenic Steroids by Hepatic Cytochrome P450 Enzymes. Steroids 1991; 56(4): 180-184

John K, and Scultz PG. Mechanistic Studies of the Oxidation of Isoniazid by Catalase Peroxidase from Mycobacterium tuberculosis. J Amer Chem Soc 1994; 116: 7425-7426

Ju C, and 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: 51-56

Ju C and Uetrecht JP. Mechanism of Idiosyncratic Drug Reactions:Reactive Metabolite Formations, Protein Binding, and the Regulation of the Immune System. Current Drug Metabolism 2002; 3:367-377

Kassahun K, Pearson P, Tang W, McIntosh I, Leung K, Elmore C, Dean D, Wang R, Doss G, and Baillie TA. Studies on the Metabolism of Troglitazone to a Reactive Intermediate in vitro and in vivo. Evidence for novel Biotransformation Pathways Involving Quinone Methide Formation and Thiazolidinedione Ring Scission. Chem Res Toxicol 2001; 14: 62-70

Kalgutkar AS, Nguyen HT, Vaz ADN, Doan A, Dalvie DK, McLeod DG, and Murray JC. In vitro Metabolism Studies on the Isoxazole Ring Scission in the Anti-Inflammatory Agent Leflunomide to its Active alpha-Cyanoenol Metabolite A771726: Mechanistic Similarities with the Cytochrome P450- Catalysed Dehydration of Aldoximes. Drug Metab Dispos 2003; 31(10):1240-1250

Kennedy GL. Biological effects of Acetamide, Formamide, and their Mono and Dimethyl Derivatives: An Update. Critical Reviews in Toxicology 2001; 31(2): 139222

White INH, and Matteis FD. The role of CYP Forms in the Metabolism and Metabolic activation of HCFC's and other Halocarbons. Toxicology Letters 2001; 124: 121-128

Knowles SR, Shapiro LE, and Shear NH. Reactive Metabolites and Adverse Drug Reactions. Clinical Reviews in Allergy and Immunology 2003; 24: 229-238

Kolberg M, BleifUss G, Grslund A, Sjberg BM, Lubitz W, Lendzian F, and Lassmann G. Protein Thiyl Radicals Observed by EPR Spectroscopy. Archives of Biochemistry and Biophysics 2002; 403(1): 141-144

Lanza DL, Code E, Crespi CL, Gonzalez FJ, and Yost GS. Specific Dehydrogenation of 3-Methylindole and epoxidation of naphthalene by recombinant human CYP2F1 expressed in lymphoblastoid cells. Drug Metab Dispos 1999; 27(7):798-803

Laurent A, Perdu-Durand E, alary J, Debrauwer L, and Cravedi JP. Metabolism of 4-Hydroxynonenal, a Cytotoxic Product of Lipid Peroxidation, in Rat Precision-Cut Liver Slices. Toxicol Lett 2000; 114(1-3): 203-214

Lazarou J, Pomeranz BH, and Corey PN. Incidence of Adverse Drug Reactions in Hospitalized Patients. JAMA 1998; 279(15): 1200-1205

Li AP. A Review of the Common Properties of Drugs with Idiosyncratic Hepatotoxicity and the "Multiple Determinant Hypothesis" for the Manifestation of Idiosyncratic Drug Toxicity. Chemico-Biological Interactions 2002; 142: 7-23

Li C, Olurinde MO, Hodges LM, Grillo MP and Benet LZ. Covalent Binding of 2-Phenylpropionyl-S-Acyl-CoA Thioester to Tissue Proteins in vitro. Drug Metab Dispos 2003; 31(6): 727-730

Li C, Grillo MP, and Benet LZ. In vitro Studies on the Chemical Reactivity of 2,4-Dichlorophenoxyacetyl-S-Acyl CoA Thioester. Toxicology and Applied Pharmacology 2003; 187(2): 101-109

Lindqvist T, Kenne L, and Lindeke B. On the chemistry of the Reaction between N-Acetylcysteine and 4-[(4-Ethoxyphenyl)imino]-2,5-Cyclohexadien-1-one, an Ethoxyaniline Metabolite formed during Peroxidase Reactions. Chem Res Toxicol 1991; 494: 489-496

Lord PG. Progress in Applying Genomics in Drug Development. Toxicology Letters 2004; 149(1-3): 371-375

Madden S, Maggs JL, and Park BK. Bioactivation of Carbamazepine in the Rat in vivo. Evidence for the Formation of Reactive Arene Oxides. Drug Metab Dispos 1996; 24(4): 469-479

Madden S, Spaldin V Hayes RN, Woolf TF, Pool WF, and Park BK. Species Variation in the Bioactivation of Tacrine by Hepatic Microsomes. Xenobiotica 1995; 25(1): 103-106

Maggs JL, Naisbitt DJ, Tettey JNA, Pirmohamed M, and Park BK. Metabolism of Lamotrigine to a Reactive Arene Oxide Intermediate. Chem Res Toxicol 2000; 13(11): 1075-1081

Maggs JL and Park BK. Drug Protein Conjugates XVI. Studies of Sorbinil Metabolism: Formation of 2-Hydroxysorbinil and Unstable Protein Conjugates.

Biochem Pharmacol 1988; 37(4): 743-748

Maggs JL, Kitteringham NR, Breckenridge AM, and Park BK. Autoxidative Formation of a Chemically Reactive Intermediate from Amodiaquine, a Myelotoxin and Hepatotoxin in Man. Biochem Pharmacol 1987; 36(13): 20612062

Martin AM, Nolan D, Gaudieri S, Almedia CA, Nolan R, James I, Carvalho F, Philips E, Christiansen FT, Purcell AW, McClusky J, and Mallal S. Predisposition to Abacavir Hypersensitivity Conferred by HLA-B 5701 and Haplotypic Hsp-Hom Variant. Proceedings of the National Academy of Sciences 2004; 101(12): 41804185

Martin JL, Kenna JG, Martin BM, Thomassen D, Reed GF, and Pohl LR. Halothane Hepatitis Patients have Serum Antibodies that React with Protein Disulfide Isomerase. Hepatology 1993; 18(4): 858-863

Martinat C, Amar C, Dansette PM, Leclaire J, Lopez Garcia P, Do Cao T, Nguyen HN, Mansuy D. In vitro Metabolism of Isaxonine Phosphate: Formation of Two metabolites, 5-Hydroxyisoaxonine and 2-Aminopyrimidine, and Covalent Binding to Microsomal Proteins. Eur J of Pharmacology 1992; 228(1): 63-71

Matzinger P. Tolerance Danger, and the Extended Family. Ann Rev Immunol 1994;12: 991-1045

Melnick RL. Carcinogenicity and Mechanistic Insights on the Behavior of Epoxides and Epoxide Forming Chemicals. Annals of NY Acad Sci 2002; 982: 177-189

Mile B. Free Radical Participation in Organic Chemistry: Electron Spin Resonance (ESR) Studies of Their Structures and Reactions. Current Organic Chemistry 2000; 4: 55-83

Moncada C, Torres V Vargese G, Albano E, and Israel Y. Ethanol-Derived Immunoreactive Species Formed by Free Radical Mechanisms. Molecular Pharmacology 1994; 46(4): 786-91

Miyamoto G, Zahid N, and Uetrecht JP. Oxidation of Diclofenac to Reactive Intermediates by Neutrophils, Myeloperoxidase, and Hypochlorous acid. Chem Res Toxicol 1997; 10: 414-419

Murray M, Hetnarski K, and Wilkinson CF. Selective Inhibitory Interactions of Alkoxymethylenedioxybenzenes towards Mono-Oxygenase Activity in Rat Hepatic Microsomes. Xenobiotica 1985; 15(3): 369-379

Naisbitt DJ, Hough SJ, Gill HJ, Pirmohamed M, Kitteringham NR, and Park BK. Cellular Disposition of Sulphamethoxazole and its Metabolites: Implications for Hypersensitivity. Br J Pharmacology 1999; 126: 1393-1407

Naisbitt DJ, O'Neill P, Pirmohamed M, and Park BK. Synthesis and Reactions of Nitroso Sulphamethoxazole with Biological Nucleophiles: Implications for Immune Mediated Toxicity. Bioorganic & Medicinal Chemistry Letters 1996; 6(13): 1511-1516

Nelson SD. Molecular Mechanisms of Adverse Drug Reactions. Current Therapeutic Research 2001; 62(12): 885-899

Nguyen M, Claparols C, Bernadou J, and Meunier B. A Fast Efficient MetalMediated Oxidation of Isoniazid and Identification of Isoniazid -NAD(H) Adducts. CHEMBIOCHEM 2001; 2: 877-883

Nunez-Vergara LJ, Farais D, Bollo S, and Sequella JA. An Electrochemical Evidence of Free Radicals Formation from Flutamide and its Reactivity with Endo/Xenobiotics of Pharmacological Relevance. Bioelectrochemistry 2001; 53(1):103-110

Olson H, Betton G, Robinson D, Thomas K, Monro Akolaja G, Lilly P, Sanders J, Sipes G, Bracken W, Dorato M, Van Deun K, Smith P, Berger B, and Heller A. Concordance of the Toxicity of Pharmaceuticals in Humans and Animals.

Regulatory Toxicology and Pharmacology 2000; 32: 56-67

Ortiz De Montellano PR. Free Radical Modification of Prosthetic Heme Groups. Pharmac Ther 1990; 48: 95-120

Ostdal H, Anderson HJ, Davies MJ. Formation of Long Lived Radicals on Proteins by Radical Transfer from Heme Enzymes-A Common Process? Archives of Biochemistry and Biophysics 1999; 362(1): 105-112

Park BK, Kitteringham NR, Powell H, and Pirmohamed M. Advances in Molecular Toxicology-Towards Understanding Idiosyncratic Drug Reactions. Toxicology 2000; 153: 39-60

Pirmohamed M, Naisbitt DJ, Gordon F, and Park BK. The Danger Hypothesis-Potential Role in Idiosyncratic Drug Reactions. Toxicology 2002;181-182: 55-63

Pumford NR, Martin BM, Thomassen D, Burris JA, Kenna JG, Martin JL, and Pohl LR. Serum Antibodies from Halothane Hepatitis Patients React with the Rat Endoplasmic Reticulum Protein ERp72. Chem Res Toxicol 1993; 6: 609-615

Rosemond MJC, and Walsh JS. Human Carbonyl Reduction Pathways and a Strategy for their Study In vitro. Drug Metab Rev 2004; 36(2): 335-361

Salustio BC, Sabordo L, Evans AM, and Nation RL. Hepatic Dispositon of Electrophilic Acyl Glucuronide Conjugates. Current Drug Metabolism 2000; 1: 163-180

Scott AM, Powell GM, Upshall DG, and Curtis CG. Pulmonary Toxicity of Thioureas in the Rat. Environmental Health Perspectives 1990; 85: 43-50

Selkirk JK, and Tennant RW. Toxicogenomics: Impact on Human Health. Pure and Applied Chemistry 2003; 75(11-12): 2413-2414

Sillanaukee P, Hurme L, Tuominen J, Ranta E, Nikkari S, and Seppa K. Structural Characterization of Acetaldehyde adducts formed by a Synthetic Peptide Mimicking the N-terminus of Hemoglobin ß-Chain under Reducing and Nonreducing Conditions. Eur J Biochem 1996; 249: 30-36

Singh S, and Dryhurst G. Interactions between 5,6-Dihydroxytryptamine and Cysteine. Bioorganic Chemistry 1993; 19(3): 274-82

Sinha BK. Activation of Hydrazine Derivatives to Free Radicals in the Perfused Rat Liver: A Spin Trapping Study. Biochimica et Biophysica Acta 1987; 924(2): 261-9

Sipe HJ, Jaszewski AR, and Mason RP. Fast Flow EPR Spectroscopic Observation of the Isoniazid, Iproniazid, and Phenylhydrazine Hydrazyl Radicals. Chem Res Toxicol 2004; 17: 226-233

Sorg O. Oxidative Stress: Theoretical Model or a Biological Reality ? Comptes Rendus Biologies 2004; 327: 649-662

Soriani M, Pietraforte D, Minetti M. Antioxidant Potential of Anaerobic Human Plasma: Role of Serum Albumin and Thiols as Scavengers of Carbon Radicals.

Archives of Biochemistry and Biophysics 1994; 312(1): 180-188

Spah-Langguth H, and Benet LZ. Acyl Glucuronides Revisited: Is the Glucuronidation Process a Toxification as well as a Detoxification Mechanism ?. Drug Metab Rev 1992; 24(1): 5-48

Stiborova M, Frei E, Weissler M, and Schmeiser HH. Human Enzymes Involved in the Metabolic Activation of Carcinogenic Aristolochic Acids: Evidence for Reductive Activation by Cytochromes P450 1A1 and 1A2. Chem Res Toxicol 2001; 14:1128-1137

Stohs SJ. The Role of Free Radicals in Toxicity and Disease. Journal of Basic & Clinical Physiology & Pharmacology 1995; 6(3-4): 205-228

Thomassen D, Knebel N, Slattery JT, McClanahan RH and Nelson S. Reactive Intermediates in the Oxidation of Menthofuran by Cyochromes P-450. Chem Res Toxicol 1992: 5: 123-130

Thompson DC, Perera K, and London R. Spontaneous Hydrolysis of 4-Trifluoromethylphenol to a Quinone Methide and Subsequent Protein Alkylation. Chemico- Biological Interactions 2000; 126: 1-14

Uetrecht JP. Bioactivation In: Lee JS, Obach RS, and Fisher MB. Drug Metabolizing Enzymes. Cytochrome P450 and Other Enzymes in Drug Discovery and Development. : New York: Marcel Decker; 2003: 87-145

Uetrecht JP. Is it Possible to More Accurately Predict which Drug Candidates will cause Idiosyncratic Reactions ?. Current Drug Metabolism 2000;1:133-141

Uetrecht JP, Zahid N, and Whitefield D. metabolism of Vesnarinone by Activated Neutrophils: Implications for Vesnarinone-Induced Agranulocytosis. J

Pharmacol Exp Ther 1994; 270(3): 865-872

Van Roon EN, Jansen TLTA, Houtman NM, Spoelstra P, Brouwers JRBJ. Leflunomide for the Treatment of Rheumatoid Arthritis in Clinical Practice: Incidence and Severity of Hepatotoxicity. Drug Safety 2004; 27(5): 345-352

Vasquez-Vivar J and Augusto O. Oxidative Activity of Primaquine Metabolites on Rat Ethrocytes In vitro and In vivo. Biochemical Pharmacology 1994; 47(2): 309316

Waldhauser L, and Uetrecht J. Oxidation of Propylthiouracil to Reactive Metabolites by Activated Neutrophils. Implications for Agranulocytosis. Drug Metab Dispos 1991; 19(2): 354-9

Walgren JL and Thompson DC. Application of Proteomic Technology in the Drug Development Process. Toxicology Letters 2004; 149(1-3): 377-385

Wallace KB. Doxorubicin - Induced Cardiac Mitochondrionopathy. Pharmacology & Toxicology. 2003; 93(3): 105-115

Walsh JS, Reese M, and Thurmond LM. The Metabolic Activation of Abacavir by human Liver Cytosol and Expressed Human Alcohol Dehydrogenase Isozymes. Chemico-Biological Interactions 2002; 142(1-2): 135-154

Ward F, and Daly M. Hepatic Disorders. In: Lee A. Adverse Drug Reactions Pharmaceuticl Press 2001: 77-97.

Zanni MP, von Greyerz S, Schnyder B, Brander KA, Frutig K, Hari Y, Valitutti S, and Pichler WJ. HLA Restricted Processing-and Metabolism -Independent Pathway of Drug Recognition by Human ■, T Lymphocytes. J Clin Invest 1998; 102(8): 1591-1598

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