The Immunologic and Metabolic Basis of Drug Hypersensitivities

Pohl, Lance R.; Satoh, Hiroshi; Christ, David D.; Kenna, J G

doi:10.1146/annurev.pa.28.040188.002055

Cited by 207 publications

(78 citation statements)

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“…Several lines of evidence indicate a direct involvement of the immune system in the development of sulfonamide-induced CDR (Warrington et al, 1983;Hertl et al, 1995;Mauri-Hellweg et al, 1995;Schnyder et al, 1997;Svensson et al, 2001). Although most drugs, including sulfonamides and sulfones, are not inherently immunogenic, they may be recognized as an antigen/immunogen after conjugation with protein (Pohl et al, 1988;Park et al, 1998;Uetrecht, 1999;Naisbitt et al, 2003). Immune responses may then be targeted against either the drug moiety of the conjugate or the carrier protein molecule of the adduct (Park and Kitteringham, 1990).…”

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confidence: 99%

Characterization of the Formation and Localization of Sulfamethoxazole and Dapsone-Associated Drug-Protein Adducts in Human Epidermal Keratinocytes

Roychowdhury

Vyas²,

Reilly³

et al. 2005

J Pharmacol Exp Ther

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Sulfonamide-and sulfone-induced hypersensitivity reactions are thought to be mediated through bioactivation of parent drug molecule(s) to their respective reactive metabolite(s). Recent studies have demonstrated that keratinocytes can bioactivate sulfonamides and sulfones. Using enzyme-linked immunosorbent assay and hapten-specific rabbit antisera developed in our laboratory, we found that incubation of either normal human epidermal keratinocytes (NHEKs) or an immortalized human keratinocyte cell line (HaCaT) with sulfamethoxazole (SMX) or dapsone (DDS) resulted in the formation of drug/metabolite protein adducts. The formation of these adducts with SMX was increased in the presence of ascorbic acid, whereas N-acetylcysteine decreased adduct formation with both SMX and DDS. Adduct formation was confirmed using confocal microscopy when NHEKs were incubated with SMX, DDS, or their respective arylhydroxylamine metabolites. Cellular distribution of adducts was compared in permeable versus nonpermeable NHEKs. Exposure to SMX, DDS, or dapsone hydroxylamine resulted in the formation of intracellular adducts, whereas SMX hydroxylamine also resulted in the presence of adducts on the cell surface. In summary, our work shows that keratinocytes can bioactivate SMX/DDS to form drug-protein adducts, which may be acquired by antigen-presenting cells upon keratinocyte cell death, evoking an immune response. In addition, keratinocytes may themselves present antigen to hapten-specific cytotoxic T lymphocytes. Furthermore, our results also suggest that different sulfonamides/sulfones may have different protein targets for in situ haptenation in keratinocytes.

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confidence: 99%

Characterization of the Formation and Localization of Sulfamethoxazole and Dapsone-Associated Drug-Protein Adducts in Human Epidermal Keratinocytes

Roychowdhury

Vyas²,

Reilly³

et al. 2005

J Pharmacol Exp Ther

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“…This adverse drug reaction is thought to have an immunological basis ; previous studies have implicated an immune response to trifluoroacetylated hepatic protein antigens [2]. Trifluoroacetyl-protein adducts (CF,CO-proteins) arise through covalent modification of target proteins by the acyl halide intermediate CF,COCl that is elicited upon oxidative, cytochrome-P450-dependent metabolism of halothane and also other structurally closely related compounds [3 -71.…”

mentioning

confidence: 99%

Identification of the dihydrolipoamide acetyltransferase subunit of the human pyruvate dehydrogenase complex as an autoantigen in halothane hepatitis

Christen

Quinn

Yeaman

et al. 1994

European Journal of Biochemistry

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Trifluoroacetylated (CF,CO-) proteins, elicited upon exposure of animals or humans to halothane, were recognized by anti-CF,CO antibody, monospecific for the hapten derivative W-trifluoroacetyl-L-lysine. Anti-CF,CO antibodies cross-reacted with the dihydrolipoamide acetyltransferase (E2 subunit) of pyruvate dehydrogenase, indicating that epitopes on the E2 subunit of pyruvate dehydrogenase molecularly mimic those on CF,CO-proteins. Lipoic acid, the prosthetic group of the E2 subunit of pyruvate dehydrogenase was essential in this process, in that only the lipoylated form of the recombinantly expressed inner lipoyl domain of the human E2 subunit of pyruvate dehydrogenase, but not the unlipoylated form, was recognized by anti-CF,CO antibody. Furthermore, based on a high degree of structural relatedness, both CF,CO-Lys and (6RS)-lipoic acid, as well as the lipoylated peptide ETDKo,,,,,,ATIG specifically inhibited the recognition by anti-CF,CO antibody of the E2 subunit of pyruvate dehydrogenase, of trifluoroacetylated rabbit serum albumin and of human liver CF,CO-proteins. In sera of patients with halothane hepatitis, autoantibodies with properties identical to those of anti-CF,CO antibody were identified which could not discriminate between CF,CO-proteins and the E2 subunit of pyruvate dehydrogenase. These data suggest that the E2 subunit pyruvate of dehydrogenase is an autoantigen in halothane hepatitis and that molecular mimicry of CF,CO-proteins by the E2 subunit of pyruvate dehydrogenase is due to the similar structures of CF,CO-Lys and lipoic acid.Halothane hepatitis is a potentially severe and life-threatening form of hepatic damage which may occur in humans exposed to the inhalation anesthetic halothane (CF,CHBrCl) [l, 21. This adverse drug reaction is thought to have an immunological basis ; previous studies have implicated an immune response to trifluoroacetylated hepatic protein antigens [2]. Trifluoroacetyl-protein adducts (CF,CO-proteins) arise through covalent modification of target proteins by the acyl halide intermediate CF,COCl that is elicited upon oxidative, cytochrome-P450-dependent metabolism of halothane and also other structurally closely related compounds [3 -71. In fact, with halothane and 2,2-dichloro-l,l,l-trifluoroethane (HCFC 123) as substrates, the predominant adduct formed in the process has been identified by 19F-NMR as W-trifluoroacetyl-L-lysine (CF,CO-Lys detected in the livers of halothane-exposed rats, rabbits, guinea pigs and mice [6,[8][9][10][11] and also in liver biopsies of halothane-exposed humans [12,13]. In halothane-exposed rats, CF,CO-proteins are found in centrilobular liver sections [6], on the surface of hepatocytes [8], within Kupffer cells [14], in liver microsomal membranes [6, 1.51 and, at low levels, disseminated in the kidneys [6], the heart [16] and the testes [17]. Furthermore, exposure of rats to the newer volatile anesthetics enflurane and isoflurane [18, 191, or to pentahaloethane-based candidate replacements of chlorofluorocarbons such as HCFC 123 [5-71,...

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“…In several of these cases, the mechanism for HLA/MHC-dependent, T-cell stimulation is thought to involve formation of an electrophilic reactive metabolite (RM) via bioactivation of the drug. The electrophilic RM reacts with a self-protein or peptide to generate a hapten, which then undergoes antigen processing to a novel MHC ligand that is trafficked to the cell surface, where it activates antigen-specific T cells (Pohl et al, 1988;Pichler et al, 2002). Haptenization via RM formation in peripheral blood cells has also been implicated in agranulocytosis associated with several structurally diverse drugs such as aminopyrine, clozapine, sulfamethoxazole, ticlopidine, methimazole, etc.…”

Section: Perspectivementioning

confidence: 99%

Immune-Mediated Agranulocytosis Caused by the Cocaine Adulterant Levamisole: A Case for Reactive Metabolite(s) Involvement

Wolford

McDonald²,

Eng³

et al. 2012

Drug Metab Dispos

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ABSTRACT:The United States Public Health Service Administration is alerting medical professionals that a substantial percentage of cocaine imported into the United States is adulterated with levamisole, a veterinary pharmaceutical that can cause blood cell disorders such as severe neutropenia and agranulocytosis. Levamisole was previously approved in combination with fluorouracil for the treatment of colon cancer; however, the drug was withdrawn from the U.S. market in 2000 because of the frequent occurrence of agranulocytosis. The detection of autoantibodies such as antithrombin (lupus anticoagulant) and an increased risk of agranulocytosis in patients carrying the human leukocyte antigen B27 genotype suggest that toxicity is immune-mediated. In this perspective, we provide an historical account of the levamisole/cocaine story as it first surfaced in 2008, including a succinct review of levamisole pharmacology, pharmacokinetics, and preclinical/clinical evidence for levamisole-induced agranulocytosis. Based on the available information on levamisole metabolism in humans, we propose that reactive metabolite formation is the rate-limiting step in the etiology of agranulocytosis associated with levamisole, in a manner similar to other drugs (e.g., propylthiouracil, methimazole, captopril, etc.) associated with blood dyscrasias. Finally, considering the toxicity associated with levamisole, we propose that the 2,3,5,6-tetrahydroimidazo[2,1-b]thiazole scaffold found in levamisole be categorized as a new structural alert, which is to be avoided in drug design.

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The Immunologic and Metabolic Basis of Drug Hypersensitivities

Cited by 207 publications

References 0 publications

Characterization of the Formation and Localization of Sulfamethoxazole and Dapsone-Associated Drug-Protein Adducts in Human Epidermal Keratinocytes

Characterization of the Formation and Localization of Sulfamethoxazole and Dapsone-Associated Drug-Protein Adducts in Human Epidermal Keratinocytes

Identification of the dihydrolipoamide acetyltransferase subunit of the human pyruvate dehydrogenase complex as an autoantigen in halothane hepatitis

Immune-Mediated Agranulocytosis Caused by the Cocaine Adulterant Levamisole: A Case for Reactive Metabolite(s) Involvement

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