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Investigations into the mechanism of action of the toxic sesquiterpene lactones, helenalin and hymenoxon
xiii, 143 leaves : illustrations ; 29 cm
Hymenoxys odorata (bitterweed) is an economically important poisonous range plant indigenous to the southwestern United States. The sesquiterpene lactone (SL), hymenoxon, has been isolated from bitterweed and demonstrated to produce signs of bitterweed toxicosis in sheep, goats, dogs, and rabbits. The precise mechanism of action is unknown, and the present series of experiments was conducted to determine the role of two structurally-related SL, hymenoxon and helenalin, on the cytochrome P-45O-dependent monooxygenases. An additional objective was to examine the role of sulfhydryl-containing compounds in determining the toxicity associated with these compounds. Both hymenoxon and helenalin elicited minimal effects on the microsomal monooxygenases in male ICR mice, and it was concluded these enzymes do not play a central role in SL toxicity. The effect of inducing hepatic glutathione (GSH) on SL toxicity was determined in mice using L-2-oxothiazolidine-4-carboxylate (OTC), an intracellular cysteine delivery system. L-2-Oxothiazolidine-4-carboxylate pretreatment resulted in significantly greater GSH values within 2 h. Levels remained elevated at 24h. The administration of either helenalin or hymenoxon resulted in significant decreases in hepatic GSH within 1.0 and 0.25 h, respectively. Pretreatment with OTC prevented the decrease in GSH subsequent to helenalin exposure and maintained, higher levels in mice exposed to hymenoxon compared with mice receiving the toxin only. Pretreatment with OTC significantly reduced the percent lethality in mice exposed to either toxin. Hepatic and renal metallothionein (MT) levels were induced by pretreating mice and Wistar rats with cadmium, zinc, cobalt, or bismuth. Cadmium and zinc induced significant increases in both hepatic and renal MT, while cobalt and bismuth induced hepatic and renal MT levels, respectively. The lethality associated with helenalin and hymenoxon exposure was significantly reduced in response to each metal pretreatment but did not coincide with the maximal induction of MT. It was concluded the prior administration of divalent cations results in biochemical changes consistent with increased survival in SL toxicity. The mechanism of this protection is unknown and requires further experimentation.
Includes bibliographical references (leaves 129-142).