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Role of Reactive Metabolites in Drug-Induced Hepatotoxicity

  • A. Srivastava
  • J. L. Maggs
  • D. J. Antoine
  • D. P. Williams
  • D. A. Smith
  • B. K. ParkEmail author
Chapter
Part of the Handbook of Experimental Pharmacology book series (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.

Keywords

Metabolic activation Reactive metabolites Hepatotoxicity 

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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Copyright information

© Springer-Verlag Berlin Heidelberg 2010

Authors and Affiliations

  • A. Srivastava
  • J. L. Maggs
  • D. J. Antoine
  • D. P. Williams
  • D. A. Smith
  • B. K. Park
    • 1
    Email author
  1. 1.Department of Pharmacology and Therapeutics, Centre for Drug Safety Science, School of Biomedical SciencesUniversity of LiverpoolLiverpoolUK

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