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

Journal Article · Mon Feb 28 23:00:00 EST 1977 · J. Toxicol. Environ. Health; (United States)

DOI:https://doi.org/10.1080/15287397709529485· OSTI ID:7110273

Thorgeirsson, S S; Wirth, P J

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.

• Research Organization: National Institutes of Health, Bethesda, MD
• OSTI ID: 7110273
• Journal Information: J. Toxicol. Environ. Health; (United States), Journal Name: J. Toxicol. Environ. Health; (United States) Vol. 2:4; ISSN JTEHD
• Country of Publication: United States
• Language: English

Related Subjects

550200 -- Biochemistry
550500* -- Metabolism
59 BASIC BIOLOGICAL SCIENCES
AMINO ACIDS
ANALGESICS
BINDING ENERGY
BODY
CARBOXYLIC ACIDS
CARCINOGENS
CLEARANCE
COVALENCE
CYTOCHROMES
DIGESTIVE SYSTEM
DISEASES
DRUGS
ENERGY
EXCRETION
GLANDS
GLUTATHIONE
LIVER
METABOLISM
MOLECULES
NECROSIS
ORGANIC ACIDS
ORGANIC COMPOUNDS
ORGANS
PATHOLOGICAL CHANGES
PEPTIDES
PIGMENTS
POLYPEPTIDES
PROTEINS
TISSUES