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

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 microM) 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.

A Sensitive Sensor Cell Line for the Detection of Oxidative Stress Responses in Cultured Human Keratinocytes

“…Likewise, helenalin dramatically reduced the tGSH pool in the HaCaT cells. Although the effects on the cellular tGSH concentrations that were obtained using the A. montana extract or helenalin seemed to conflict with the results that were observed following exposure to cadmium, other studies have described the reduction of the cellular tGSH pool by STL, including helenalin, likely through the ROS-dependent oxidization of the cysteine pool that is required for glutathione synthesis [23]. …”

Effect of Several Sesquiterpene Lactones on Lipid Peroxidation and Glutathione Level

“…for mice of 9.85 mg/kg (5), Chapman et al (4) reported 43 mg/ kg for the same species and route of administration. Merril et al (11) found that the dose of 25 mg/kg i.p. caused the death of 60 % of tested mice.…”

“…Helenalin is a constituent of the medicinally used flower heads of Arnica species (3). Its acute toxicity, cytotoxicity (4,5), antiulcer activity (6,7) and effect on many biochemical parameters including protein synthesis, some enzymes activity (8,9) and liver glutathione level (10,11) have been investigated. There are only single reports concerning biological activity of the rest of the above mentioned lactones (1,6).…”

Arnica Flowers: Pharmacology, Toxicolgy, and Analysis of the Sesquiterpene Lactones—Their Main Active Substances

“…Among others, the specific metabolic targets are the thiol-bearing enzymes IMP dehydrogenase, DNA polymerase a, ribonucleoside reductase (33,36,38), elF-2 kinase, and the elongation factor eIF-3 (29,30). Furthermore, the compounds lower the cellular glutathione level (39,40).…”

“…Acute toxicity by helenalin has been related to hepatic glutathione levels, which are rapidly depleted by very low concentrations of helenalin (39). The oral LD 5 o values of helenalin for mammals varies form 85 mg/kg for hamster to 150 mg/kg for mouse (73).…”