Elsevier

Drug Discovery Today

Volume 8, Issue 22, 15 November 2003, Pages 1044-1050
Drug Discovery Today

Review
Idiosyncratic toxicity: the role of toxicophores and bioactivation

https://doi.org/10.1016/S1359-6446(03)02888-5Get rights and content

Abstract

Drugs and chemicals can undergo enzyme-catalyzed bioactivation reactions within cellular systems, with the formation of reactive chemical species. These reactive metabolites can lead to thiol depletion, reversible protein modification (glutathionylation and nitration), further irreversible protein adduct formation and subsequent irreversible protein damage. The incorporation of potentially reactive chemical moieties – toxicophores – within new therapeutic agents should be limited. However, this cannot always be prevented, particularly when the structural feature responsible for toxicity is also responsible for the pharmacological efficacy. The identification and further knowledge of critical levels of thiol depletion and/or covalent modification of protein will aid in the development of new drugs. Importantly, the identification of drug–thiol conjugation should provide a warning of potential problems, yet not hinder the development of a potentially therapeutically useful drug.

Section snippets

The problem – reactive metabolites?

It is generally thought that reactive, electrophilic compounds, formed either from the parent drug (e.g. a reactive quinoneimine from paracetamol) or as a consequence of increased cellular production of reactive oxygen and/or nitrogen species (hydroxyl radical, superoxide and peroxynitrite) are responsible for initiating toxicity. Reactive metabolites can cause tissue damage by direct modification of cellular proteins, such as covalent binding of the drug to the protein, or oxidation of

The solution?

The first alert to potential toxicity should be the identification of potential toxicophores within the proposed candidate compound, by the medicinal chemist or the drug metabolist. Although this is not a sufficient reason for stopping drug development at this stage, it should serve as a warning. Obviously, prevention of the release of potentially toxic drugs on the market takes a high priority. However, with the growing use and stringency of toxicity screens, there is an increased chance of

Detection of cell stress

Further knowledge of the molecular consequences of drug bioactivation, downstream from glutathione depletion and covalent binding, are required to ultimately define a drug and/or particular dose as toxic or non-toxic. Downstream molecular pathways, such as transcription factor activation, gene and protein expression, and protein degradation, will give greater insight into the underlying mechanisms of toxicity. Transcription factors (proteins involved in cellular signalling and modulation of

Transcription factor regulation

The transcription factor nuclear factor erythroid-2 related factor (Nrf2) is currently the subject of intense investigation into chemotherapy and drug toxicity. Nrf2 nuclear localization has been shown to result in the expression of numerous defensive genes, such as NAD(P)H:quinone oxidoreducatse-1 (NQO1) and heat shock proteins (HSPs) [52]. It has also been confirmed that Nrf2 associates with a novel cytoplasmic protein, Kelch-like ECH-associated protein1 (Keap1), that directly negatively

Downstream considerations

The majority of idiosyncratic drug reactions (IDRs) at initial challenge, require weeks, if not months, of chronic dosing, before they are apparent 21., 64.. This is suggestive of an accumulation or chronic depletion mechanism. For example, accumulation of a drug–protein conjugate might eventually initiate a toxic or immune reaction when the concentration of conjugate reaches a specific level. Conversely, chronic low-level reactive metabolite formation could lead to lowered antioxidant levels

Acknowledgements

We would like to thank Pfizer and the Wellcome Trust.

References (72)

  • K. Itoh

    An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements

    Biochem. Biophys. Res. Commun.

    (1997)
  • M. McMahon

    Keap1-dependent proteasomal degradation of transcription factor Nrf2 contributes to the negative regulation of antioxidant response element-driven gene expression

    J. Biol. Chem.

    (2003)
  • W.H. Heijne

    Toxicogenomics of bromobenzene hepatotoxicity: a combined transcriptomics and proteomics approach

    Biochem. Pharmacol.

    (2003)
  • T.P. Reilly

    Expression profiling of acetaminophen liver toxicity in mice using microarray technology

    Biochem. Biophys. Res. Commun.

    (2001)
  • M. Fountoulakis

    Modulation of gene and protein expression by carbon tetrachloride in the rat liver

    Toxicol. Appl. Pharmacol.

    (2002)
  • F.W. Benz

    Dose dependence of covalent binding of acrylonitrile to tissue protein and globin in rats

    Fundam. Appl. Toxicol.

    (1997)
  • J. Lazarou

    Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies

    J. Am. Med. Assoc.

    (1998)
  • M. Pirmohamed

    Adverse drug reactions: current status

    BMJ

    (1998)
  • M. Meadows

    Serious liver injury. Leading reason for drug removals, restrictions

    FDA Consum.

    (2001)
  • S. Michelson et al.

    Drug discovery, drug development and the emerging world of pharmacogenomics: prospecting for information in a data-rich landscape

    Curr. Opin. Mol. Ther.

    (2000)
  • M.A. Friedman

    The safety of newly approved medicines: do recent market removals mean there is a problem?

    J. Am. Med. Assoc.

    (1999)
  • S.D. Nelson

    Structure toxicity relationships–how useful are they in predicting toxicities of new drugs?

    Adv. Exp. Med. Biol.

    (2001)
  • W.D. Reid

    Bromobenzene metabolism and hepatic necrosis

    Pharmacology

    (1971)
  • R. Fisher

    Correlation of metabolism, covalent binding and toxicity for a series of bromobenzene derivatives using rat liver slices in vitro

    Chem. Biol. Interact.

    (1993)
  • D.E. Slaughter et al.

    Identification of epoxide- and quinone-derived bromobenzene adducts to protein sulfur nucleophiles

    Chem. Res. Toxicol.

    (1991)
  • C.V. Smith

    Free radicals in vivo. Covalent binding to lipids

    Mol. Pharmacol.

    (1984)
  • D.J. Jollow

    Bromobenzene-induced liver necrosis. Protective role of glutathione and evidence for 3,4-bromobenzene oxide as the hepatotoxic metabolite

    Pharmacology

    (1974)
  • H. Thor

    Biotransforamtion of bromobenzene to reactive metabolites by isolated hepatocytes

  • A.E. Cribb

    Adverse reactions to sulphonamide and sulphonamide-trimethoprim antimicrobials: clinical syndromes and pathogenesis

    Adverse Drug React. Toxicol. Rev.

    (1996)
  • A.E. Cribb

    Covalent binding of sulfamethoxazole reactive metabolites to human and rat liver subcellular fractions assessed by immunochemical detection

    Chem. Res. Toxicol.

    (1996)
  • B. Schnyder

    T-cell-mediated cytotoxicity against keratinocytes in sulfamethoxazole-induced skin reaction

    Clin. Exp. Allergy

    (1998)
  • B.K. Park

    Role of drug disposition in drug hypersensitivity: a chemical, molecular, and clinical perspective

    Chem. Res. Toxicol.

    (1998)
  • D.J. Naisbitt

    Cellular disposition of sulphamethoxazole and its metabolites: implications for hypersensitivity

    Br. J. Pharmacol.

    (1999)
  • U.A. Boelsterli

    Xenobiotic acyl glucuronides and acyl CoA thioesters as protein-reactive metabolites with the potential to cause idiosyncratic drug reactions

    Curr. Drug Metab.

    (2002)
  • A.A. Dunk

    Diclofenac hepatitis

    BMJ

    (1982)
  • L.J. Scully

    Diclofenac induced hepatitis: three cases with features of autoimmune chronic active hepatitis

    Dig. Dis. Sci.

    (1993)
  • Cited by (101)

    View all citing articles on Scopus
    View full text