|Green, Benedict - Ben|
Submitted to: Journal of Animal Science
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/14/2010
Publication Date: 5/1/2011
Citation: Welch, K.D., Panter, K.E., Gardner, D.R., Stegelmeier, B.L., Green, B.T., Pfister, J.A., Cook, D. 2011. The acute toxicity of the Death camas (Zigadenus spp.) alkaloid zygacine in mice, including the effect of methyllycaconitine co-administration on zygacine toxicity. Journal of Animal Science. 89(5):1650-7.
Interpretive Summary: There are many species of death camas (Zigadenus spp.) located in western North America. Poisonings generally occur during the spring when death camas is abundant while other forage species have little growth. Poisonings also occur on overgrazed ranges where better quality forage has been depleted, or when management errors result in and hungry animals being moved into death camas-infested areas. In most cases where livestock are poisoned by plants in a range setting, there are multiple poisonous plants in the area where the animals were poisoned. One common poisonous plant found growing simultaneously in the same area as death camas is low larkspur (Delphinium nuttallianum). The objectives of this study were to conduct preliminary acute toxicity studies in mice and to determine if the co-administration of methyllycaconitine (MLA), one of the major toxic alkaloids from low larkspur, exacerbates the toxicity of zygacine. In order to accomplish this objective, we characterized a number of different parameters describing the acute toxicity of zygacine in mice. The results from this study indicate that both MLA and zygacine are very toxic, with LD50 values of approximately 4.6 and 2.0 mg/kg, respectively. The LD50 value for a 1:1 mixture of MLA and zygacine (2.9 mg/kg) was different from the LD50 value of zygacine alone and MLA alone. The i.v. LD50 value of the mixture is almost half way between the individual values of each compound. However, in essence, the LD50 value for the mixture corresponds to a value of 1.45 mg/kg for each alkaloid, which is significantly lower that the LD50 for each individual compound. Consequently, these results suggest that there is an exacerbation in toxicity by combining these two toxins, at least for an acute i.v. toxicity study in mice. These results demonstrate that zygacine is a very toxic compound. We also demonstrated that zygacine is the major alkaloid in Z. paniculatus, and that zygacine accounts for the majority of the toxicity of a total alkaloid extract from death camas. In addition, we report the elimination half-life of zygacine in mice to be approximately 13 min. The results from this study provide an increased knowledge and understanding regarding the acute toxicity of death camas. This information will be useful in further developing livestock management recommendations for ranchers and in designing additional experiments to study the toxicity of death camas in livestock species.
Technical Abstract: Death camas (Zigadenus spp.) is a common poisonous plant on foothill rangelands in western North America. The steroidal alkaloid zygacine is believed to be the primary toxic component in death camas. Poisonings on rangelands generally occur in the spring when death camas is abundant while other more desirable forage species are limited in availability. In most cases where livestock are poisoned by plants in a range setting, there is more than one potential poisonous plant in that area. One common poisonous plant that is often found growing simultaneously in the same area as death camas is low larkspur (Delphinium nuttallianum). Consequently, the objectives of this study were to conduct acute toxicity studies in mice and to determine if co-administration of low larkspur will exacerbate the toxicity of death camas. We first characterized a number of different parameters describing the acute toxicity of zygacine in mice. The i.v. LD50 of total alkaloid extracts from a Utah and a Nevada collection were 2.8 ± 0.8 and 2.2 ± 0.3 mg/kg, respectively. The LD50 of zygacine administered i.v. and orally was 2.0 ± 0.2 mg/kg and 132 ± 21 mg/kg, respectively. The rate of elimination of zygacine from whole blood was determined to be 0.06 ± 0.01 / min, which corresponds to an elimination half-life of 13.0 ± 2.7 min. The i.v. LD50 of methyllycaconitine (MLA), one of the major toxic alkaloids in low larkspur, was 4.6 ± 0.5 mg/kg. In comparison, the i.v. LD50 of a 1:1 mixture of MLA and zygacine was 2.9 ± 0.7 mg/kg. The clinical signs in mice treated with this mixture were very similar to those of mice treated with zygacine alone, including the time of onset and death. These results suggest that there is not a synergistic effect of co-administering these two alkaloids intravenously in mice, however, there appears to be an additive effect. The results from this study increase knowledge and understanding regarding the acute toxicity of death camas. As combined intoxications are most likely common, this information will be useful in developing management recommendations for ranchers and in designing additional experiments to study the toxicity of death camas to livestock.