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Subcellular binding and effects on calcium homeostasis produced by acetaminophen and a nonhepatotoxic regioisomer, 3′-hydroxyacetanilide, in mouse liver

Year: 1989

Type: article

Abstract: Acetaminophen (250 mg/kg) administered intraperitoneally to fasted, phenobarbital-induced mice produced hepatotoxicity. No hepatotoxicity was observed after the administration of the regioisomer 3'-hydroxyacetanilide (600 mg/kg). Similar levels of covalent binding to liver homogenates occurred in mice receiving either acetaminophen or 3'-hydroxyacetanilide at these doses. However, subcellular fractionation techniques revealed that the acetaminophen treatment produced greater levels of covalent binding to mitochondrial proteins than 3'-hydroxyacetanilide. In addition, acetaminophen depleted mitochondrial glutathione levels more extensively than 3'-hydroxyacetanilide. Plasma membrane calcium-ATPase activity was reduced to 79.8% and 55.7% of control values at 1 h and 6 h, respectively, following the administration of acetaminophen. No inhibition of this enzyme was detected in mice receiving 3'-hydroxyacetanilide. Acetaminophen also induced alterations in mitochondrial calcium levels and decreased the ability of isolated mitochondria to sequester calcium. These effects were not produced by 3'-hydroxyacetanilide. Our results indicate that acetaminophen induces alterations in calcium homeostasis while 3'-hydroxyacetanilide does not.

Source: Journal of Biological Chemistry

DOI: 10.1016/s0021-9258(18)81731-8

Authors: M A Tirmenstein, S D Nelson

Institution: University of Washington

Language: English

Topic: Drug-Induced Hepatotoxicity and Protection

Subfield: Pharmacology

Field: Pharmacology, Toxicology and Pharmaceutics

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $3,430