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Title: Covalent binding of foreign chemicals to tissue macromolecules. [Acetaminophen]

Abstract

In vivo and in vitro covalent binding of foreign chemicals to tissue macromolecules via metabolic activation is described, using the analgesic acetaminophen as an example. Acetaminophen is metabolized through a variety of pathways. The arylating metabolite is formed by a cytochrome P-450 dependent N-hydroxylation process. The resulting hydroxamic acid is then conjugated with glutathione, and the resulting conjugate is subsequently excreted as the mercapturic acid in the urine. It is not until the glutathione concentration is reduced to about 20% of the initial concentration that covalent binding of acetaminophen to amino acids of proteins occurs and subsequent liver necrosis is seen. The extent of in vitro binding correlates with treatments that alter hepatic necrosis and in vivo binding, indicating that in vitro binding is a valid index of acetaminophen hepatotoxicity. A simple bacterial test system for detecting chemical carcinogens as mutagens is described.

Authors:
;
Publication Date:
Research Org.:
National Institutes of Health, Bethesda, MD
OSTI Identifier:
7110273
Resource Type:
Journal Article
Journal Name:
J. Toxicol. Environ. Health; (United States)
Additional Journal Information:
Journal Volume: 2:4
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; ANALGESICS; METABOLISM; CYTOCHROMES; GLUTATHIONE; MOLECULES; BINDING ENERGY; TISSUES; AMINO ACIDS; CARCINOGENS; COVALENCE; EXCRETION; LIVER; NECROSIS; BODY; CARBOXYLIC ACIDS; CLEARANCE; DIGESTIVE SYSTEM; DISEASES; DRUGS; ENERGY; GLANDS; ORGANIC ACIDS; ORGANIC COMPOUNDS; ORGANS; PATHOLOGICAL CHANGES; PEPTIDES; PIGMENTS; POLYPEPTIDES; PROTEINS; 550500* - Metabolism; 550200 - Biochemistry

Citation Formats

Thorgeirsson, S.S., and Wirth, P.J. Covalent binding of foreign chemicals to tissue macromolecules. [Acetaminophen]. United States: N. p., 1977. Web. doi:10.1080/15287397709529485.
Thorgeirsson, S.S., & Wirth, P.J. Covalent binding of foreign chemicals to tissue macromolecules. [Acetaminophen]. United States. doi:10.1080/15287397709529485.
Thorgeirsson, S.S., and Wirth, P.J. Tue . "Covalent binding of foreign chemicals to tissue macromolecules. [Acetaminophen]". United States. doi:10.1080/15287397709529485.
@article{osti_7110273,
title = {Covalent binding of foreign chemicals to tissue macromolecules. [Acetaminophen]},
author = {Thorgeirsson, S.S. and Wirth, P.J.},
abstractNote = {In vivo and in vitro covalent binding of foreign chemicals to tissue macromolecules via metabolic activation is described, using the analgesic acetaminophen as an example. Acetaminophen is metabolized through a variety of pathways. The arylating metabolite is formed by a cytochrome P-450 dependent N-hydroxylation process. The resulting hydroxamic acid is then conjugated with glutathione, and the resulting conjugate is subsequently excreted as the mercapturic acid in the urine. It is not until the glutathione concentration is reduced to about 20% of the initial concentration that covalent binding of acetaminophen to amino acids of proteins occurs and subsequent liver necrosis is seen. The extent of in vitro binding correlates with treatments that alter hepatic necrosis and in vivo binding, indicating that in vitro binding is a valid index of acetaminophen hepatotoxicity. A simple bacterial test system for detecting chemical carcinogens as mutagens is described.},
doi = {10.1080/15287397709529485},
journal = {J. Toxicol. Environ. Health; (United States)},
number = ,
volume = 2:4,
place = {United States},
year = {1977},
month = {3}
}