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Tissue selective toxicity: Introduction

  • J. R. Mitchell

Abstract

Chemically reactive metabolites have been implicated as mediators of the hepatic necrosis produced in animals by such commonly administered drugs as acetaminophen (paracetamol), phenacetin, acetanilide, furosemide, cephaloridine, iproniazid and isoniazid-acetylisoniazid (Gillette et al., 1974; Mitchell & Jollow, 1975; Mitchell et al., 1975). When these hepatotoxic drugs are appropriately radiolabelled and administered to animals over a wide dose range, they can be shown to bind covalently to hepatic macromolecules. Since they are chemically stable compounds, the finding of a covalent linkage with macromolecules of their target tissue, the liver, demonstrates that they are converted in the body into reactive alkylating, arylating or acylating agents. Pretreatment of the animals with inducers of metabolism, such as phenobarbitone, or with inhibitors of metabolism, such as piperonyl butoxide and CoCl2, similarly alters the rate of drug metabolism, the severity of hepatic necrosis and the extent of hepatic binding of radiolabelled metabolites.

Keywords

Covalent Binding Hepatic Necrosis Reactive Metabolite Liver Necrosis Mercapturic Acid 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© Macmillan Publishers Limited 1984

Authors and Affiliations

  • J. R. Mitchell
    • 1
  1. 1.Department of Medicine and Institute for Lipid ResearchBaylor College of MedicineHoustonUSA

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