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Role of Reactive Metabolites in Drug-Induced Hepatotoxicity

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Adverse Drug Reactions

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 196))

Abstract

Drugs are generally converted to biologically inactive forms and eliminated from the body, principally by hepatic metabolism. However, certain drugs undergo biotransformation to metabolites that can interfere with cellular functions through their intrinsic chemical reactivity towards glutathione, leading to thiol depletion, and functionally critical macromolecules, resulting in reversible modification, irreversible adduct formation, and irreversible loss of activity. There is now a great deal of evidence which shows that reactive metabolites are formed from drugs known to cause hepatotoxicity, such as acetaminophen, tamoxifen, isoniazid, and amodiaquine. The main theme of this article is to review the evidence for chemically reactive metabolites being initiating factors for the multiple downstream biological events culminating in toxicity. The major objectives are to understand those idiosyncratic hepatotoxicities thought to be caused by chemically reactive metabolites and to define the role of toxic metabolites.

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Abbreviations

ADRs:

Adverse drug reactions

DILI:

Drug-induced liver injury

APAP:

Acetaminophen

NAPQI:

N-acetyl-p-benzoquinoneimine

GSH:

Glutathione

ARE:

Antioxidant response element

CCl4 :

Carbon tetrachloride

NVP:

Nevirapine

INH:

Isoniazid

AQ:

Amodiaquine

AQQI:

Amodiaquine quinoneimine

ALT:

Alanine aminotransferase

AST:

Aspartate aminotransferase

ULN:

Upper limit of normal

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  1. Department of Pharmacology and Therapeutics, Centre for Drug Safety Science, School of Biomedical Sciences, University of Liverpool, Sherrington Buildings, Ashton Street, Liverpool, L69 3GE, UK

    B. K. Park

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  1. A. Srivastava
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  2. J. L. Maggs
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  3. D. J. Antoine
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  4. D. P. Williams
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  5. D. A. Smith
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  6. B. K. Park
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  1. Faculty of Pharmacy, University of Toronto, Toronto, Canada, M5S 2S2

    Jack Uetrecht (Professor of Pharmacy and Medicine, Canada Research Chair in Adverse Drug Reactions) (Professor of Pharmacy and Medicine, Canada Research Chair in Adverse Drug Reactions)

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Srivastava, A., Maggs, J.L., Antoine, D.J., Williams, D.P., Smith, D.A., Park, B.K. (2010). Role of Reactive Metabolites in Drug-Induced Hepatotoxicity. In: Uetrecht, J. (eds) Adverse Drug Reactions. Handbook of Experimental Pharmacology, vol 196. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-00663-0_7

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