Mechanisms, chemical structures and drug metabolism

L. R. Pohl, N. R. Pumford, J. L. Martin

Research output: Contribution to journalArticle

Abstract

From the studies that have been done by many laboratories over the last 2 decades, it is now clear that the toxicities produced by many drugs are due to their reactive metabolites. It is thought that, in many cases, reactive metabolites cause toxicity by binding covalently to tissue proteins. However, until recently it was difficult to identify these protein targets. Due to the development of an immunochemical approach, this problem has been overcome, as is illustrated here by studies that have been conducted on the metabolic basis of the idiosyncratic hepatitis caused by the inhalation anaesthetic halothane. The major problem to solve in the future will be to determine how protein adduct formation leads to toxicity. It is possible that protein adduct formation may alter an important cellular function or may lead to immunopathology, as is thought to occur in the case of halothane hepatitis. If an allergic reaction is suspected, purified protein targets of reactive metabolites can serve as antigens for identifying sensitized individuals. This information can be used to prevent not only an allergic reaction to the drug, but possibly cross-reactions to other drugs that are structurally related. Another important application of these studies is the design of safer alternative drugs that will not produce structurally similar toxic reactive metabolites.

Original languageEnglish (US)
Pages (from-to)98-104
Number of pages7
JournalEuropean Journal of Haematology, Supplement
Volume57
Issue number60
StatePublished - Dec 3 1996

Keywords

  • Autoantibodies
  • Drug allergy
  • Halothane hepatitis
  • Idiosyncratic drug toxicity
  • Protein adducts
  • Reactive metabolites

ASJC Scopus subject areas

  • Hematology

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    Pohl, L. R., Pumford, N. R., & Martin, J. L. (1996). Mechanisms, chemical structures and drug metabolism. European Journal of Haematology, Supplement, 57(60), 98-104.