Protection of ethanol-mediated acetaminophen hepatotoxicity by triacetyloleandomycin, a specific inhibitor of CYP3A

Vesvolod E. Kostrubsky, Juliana G. Szakacs, Elizabeth H Jeffery, Sheryl G. Woods, William J. Bement, Steven A. Wrighton, Peter R. Sinclair, Jacqueline F. Sinclair

Research output: Contribution to journalArticlepeer-review

Abstract

Cytochrome P450 2E (CYP2E) is considered responsible for ethanol- mediated increases in acetaminophen (APAP) hepatotoxicity. However, it has been shown in cultured human and rat hepatocytes and intact rats that ethanol induces CYP3A in addition to CYP2E. Therefore, an investigation was made in rats to see whether or not an inhibitor of CYP3A, triacetyloleandomycin (TAO), would protect against ethanol-mediated increases in APAP hepatotoxicity. Rats, treated with 6.3 percent ethanol in the Lieber-DeCarli diet for 7 days, were administered APAP (1g/kg, ig) 11 hrs after removal of the diet. Triacetyloleandomycin (500 mg/kg, saline solution) was injected ip 2 hrs before the administration of APAP. In rats pretreated with ethanol, treatment with APAP for 7 hrs resulted in focal centrilobular congestion and steatosis. Triacetyloleandomycin completely prevented the histological liver damage in all 8 animals. These results suggest that, in ethanol-treated rats, CYP3A plays a major role in increasing APAP hepatotoxicity.

Original languageEnglish (US)
Pages (from-to)57-62
Number of pages6
JournalAnnals of Clinical and Laboratory Science
Volume27
Issue number1
StatePublished - Jan 22 1997

ASJC Scopus subject areas

  • Microbiology
  • Immunology and Allergy
  • Pathology and Forensic Medicine
  • Immunology
  • Molecular Biology
  • Hematology
  • Clinical Biochemistry
  • Medical Laboratory Technology

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