Acetaminophen hepatotoxicity: studies on the mechanism of cysteamine protection

Journal Article · Sun Mar 30 04:00:00 EST 1986 · Toxicol. Appl. Pharmacol.; (United States)

DOI:https://doi.org/10.1016/0041-008X(86)90329-7· OSTI ID:5737026

Miller, M G; Jollow, D J

Inhibition of the cytochrome P-450-dependent formation of the acetaminophen-reactive metabolite was investigated as a possible mechanism for cysteamine protection against acetaminophen hepatotoxicity. Studies in isolated hamster hepatocytes indicated that cysteamine competitively inhibited the cytochrome P-450 enzyme system as represented by formation of the acetaminophen-glutathione conjugate. However, cysteamine was not a potent inhibitor of glutathione conjugate formation (Ki = 1.17 mM). Cysteamine also weakly inhibited the glucuronidation of acetaminophen (Ki = 2.44 mM). In vivo studies were in agreement with the results obtained in isolated hepatocytes; cysteamine moderately inhibited both glucuronidation and the cytochrome P-450-dependent formation of acetaminophen mercapturate. The overall elimination rate constant (beta) for acetaminophen was correspondingly decreased. Since cysteamine decreased both beta and the apparent rate constant for mercapturate formation (K'MA), the proportion of the dose of acetaminophen which is converted to the toxic metabolite (K'MA/beta) was not significantly decreased in the presence of cysteamine. Apparently, cysteamine does inhibit the cytochrome P-450-dependent formation of the acetaminophen-reactive metabolite, but this effect is not sufficient to explain antidotal protection.

• Research Organization: Medical Univ. of South Carolina, Charleston
• OSTI ID: 5737026
• Journal Information: Toxicol. Appl. Pharmacol.; (United States), Journal Name: Toxicol. Appl. Pharmacol.; (United States) Vol. 1; ISSN TXAPA
• Country of Publication: United States
• Language: English

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560301* -- Chemicals Metabolism & Toxicology-- Cells-- (-1987)
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.
AMINES
ANIMAL CELLS
ANIMALS
BIOCHEMICAL REACTION KINETICS
BIOLOGICAL EFFECTS
BODY
CYTOCHROME OXIDASE
DIGESTIVE SYSTEM
DRUGS
ENZYMES
GLANDS
GLUTATHIONE
HAEM DEHYDROGENASES
HAMSTERS
IN VITRO
INHIBITION
KINETICS
LIVER
LIVER CELLS
MAMMALS
MEA
METABOLISM
NECROSIS
ORGANIC COMPOUNDS
ORGANIC SULFUR COMPOUNDS
ORGANS
OXIDOREDUCTASES
PATHOLOGICAL CHANGES
PEPTIDES
POLYPEPTIDES
PROTEINS
RADIOPROTECTIVE SUBSTANCES
REACTION KINETICS
RODENTS
SOMATIC CELLS
THIOLS
TOXICITY
VERTEBRATES