Role of glutathione in the toxicity of the sesquiterpene lactones hymenoxon and helenalin

J. C. Merrill, H. L. Kim, S. Safe, C. A. Murray, M. A. Hayes

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

Hymenoxon and helenalin are toxic sesquiterpene lactones present in the toxic range plants Hymenoxys odorata and Helenium microcephalum. Helenalin (25 mg/kg) or hymenoxon (30 mg/kg) administered to immature male ICR mice caused a rapid decrease in hepatic glutathione levels and were lethally toxic to greater than 60% of the animals within 6 d.L-2-Oxothiazolidine 4-carboxylate (OTC), a compound that elevates cellular glutathione levels, administered to mice 6 or 12 h before either helenalin or hymenoxon protected against hepatic glutathione depletion and the lethal toxicity of these toxins. OTC administered at the same time as the sesquiterpene lactones was not protective, suggesting that the critical events against which glutathione is protective occur within the first 6 h. In primary rat hepatocyte cultures, hymenoxon and helenalin (4-16 μM) caused a rapid lethal injury as determined by the release of lactate dehydrogenase. Cotreatment of cultures with N-acetylcysteine at high concentrations (4 mM) afforded significant protection against lethal injury by both toxins. In contrast, BCNU, which inhibits glutathione reductase, or diethylmaleate, which depletes hepatocellular glutathione, potentiated the hepatotoxicity of helenalin and hymenoxon in monolayer rat hepatocytes. These studies suggest that the in vivo and in vitro toxicity of hymenoxon and helenalin is strongly dependent on hepatic glutathione levels, which hymenoxon and helenalin rapidly deplete at very low concentrations.

Original languageEnglish (US)
Pages (from-to)159-169
Number of pages11
JournalJournal of Toxicology and Environmental Health
Volume23
Issue number2
DOIs
StatePublished - Feb 1988

ASJC Scopus subject areas

  • Toxicology
  • Pollution

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