Comparison of the acute toxicity of zygacine versus zygadenine

Authors: Welch, Kevin; GARDNER, DALE - Retired ARS Employee; Lee, Stephen; Stonecipher, Clinton - Clint; Cook, Daniel

Submitted to: Toxicon
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/17/2024
Publication Date: 7/20/2024
Citation: Welch, K.D., Gardner, D.R., Lee, S.T., Stonecipher, C.A., Cook, D. 2024. Comparison of the acute toxicity of zygacine versus zygadenine. Toxicon. 248: Article 108037. https://doi.org/10.1016/j.toxicon.2024.108037.
DOI: https://doi.org/10.1016/j.toxicon.2024.108037

Interpretive Summary: Death Camas (Zigadenus spp.) is a common poisonous plant found throughout North America in diverse habitats. The toxic alkaloids in foothill death camas are zygadenine, esters of zygadenine, with zygacine, the 3-acetyl ester of zygadenine, being the most abundant. Two additional esters of zygadenine that are found primarily in the floral parts of foothill death camas are 3-angeloylzygadenine and 3-veratroylzygadeine. The objective of this study was to determine if there is a difference in the acute toxicity of zygacine and zygadenine in mice and sheep. Additionally, zygadenine, 3-angeloylzygadenine and 3-veratroylzygadenine, were evaluated for their acute toxicity in mice. All three esters of zygacine tested were more toxic than zygadenine, with the following rank order of toxicity in the mouse assay: zygadenine < zygacine < angeloylzygadenine < veratroylzygadenine. Similar to the results of the mouse experiments, zygacine was significantly more toxic than zygadenine in sheep dosed IV with pure compounds. Overall, these data indicate that zygacine is more toxic than zygadenine when administered intravenously. The results of this study also demonstrate a clear structure function relationship with the toxicity of zygadenine and its esters directly correlating with the size of the R group ester linkage.

Technical Abstract: Foothill death camas (Zigadenus paniculatus) is a common poisonous plant found throughout western North America. The toxic alkaloids in foothill death camas are zygadenine, esters of zygadenine, with zygacine, the 3-acetyl ester of zygadenine, often being the most abundant. Two additional esters of zygadenine that are found primarily in the floral parts of foothill death camas are 3-angeloylzygadenine and 3-veratroylzygadeine. Recent research has shown that very little zygacine is detected in the blood of animals dosed with zygacine. A recent investigation into the metabolism of zygacine demonstrated that zygacine is rapidly metabolized to zygadenine, demonstrating a clear first pass effect. The objective of this study was to determine if there is a difference in the acute toxicity of zygacine and zygadenine to mice and sheep. Additionally, two other esters of zygadenine, 3-angeloylzygadenine and 3-veratroylzygadenine, were evaluated for their acute toxicity in a mouse IV LD50 assay. All three esters of zygacine tested were more toxic than zygadenine, with the following rank order of toxicity in the mouse IV LD50 assay: zygadenine-HCl (59.5 mg/kg) < zygacine-HCl (1.6 mg/kg) < angeloylzygadenine-HCl (1.0 mg/kg) < veratroylzygadenine-HCl (0.5 mg/kg). Similar to the results of the mouse experiments, zygacine-HCl was significantly more toxic than zygadenine-HCl in sheep dosed IV with pure compounds. Sheep dosed with 1.25 mg/kg zygacine-HCl showed severe clinical signs of poisoning. Whereas a dose of 12.5 mg/kg zygadenine-HCl was required to elicit a similar onset and severity of clinical signs. Overall, these data indicate that zygacine is more toxic than zygadenine when administered IV, when first pass metabolism is bypassed.