|Green, Benedict - Ben|
|Pfister, James - Jim|
Submitted to: Journal of Animal Science
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/6/2008
Publication Date: 7/25/2008
Publication URL: http://www.pprl.ars.usda.gov
Citation: Welch, K.D., Panter, K.E., Gardner, D.R., Green, B.T., Pfister, J.A., Cook, D., Stegelmeier, B.L. 2008. The effect of 7, 8-Methylenedioxylycoctonine -Type Diterpenoid Alkaloids on the Toxicity of Ethyllycaconitine in Mice. Journal of Animal Science, J. Anim. Sci. 86:2761-2770. Interpretive Summary: The results of this study confirm previous reports that MSAL-type alkaloids such as MLA are the primary factors responsible for the toxicity of larkspur plants. However, in plants that contain large quantities of MDL-type alkaloids, these less toxic alkaloids also appear to enhance the overall toxicity of the plant and must be considered when predicting potential toxicity of larkspur populations. Consequently when chemical analyses are performed on larkspur plants to assess their toxic potential, the concentration of both the MSAL and MDL-type alkaloids should to be determined, with more weight given to the MSAL-type alkaloids. We used a rodent model in this study. Consequently, similar experiments need to be performed in cattle to verify these results.
Technical Abstract: Larkspur plants contain numerous norditerpenoid alkaloids which include the 7, 8-methylenedioxylycoctonine (MDL-type) alkaloids and the N-(methylsuccinimido) anthranoyllycoctonine (MSAL-type) alkaloids. The MSAL-type alkaloids are generally much more toxic (typically > 20x). The toxicity of many tall larkspurs such as Delphinium barbeyi has bee attributed to its high concentration of MSAL-type alkaloids including methyllycaconitine (MLA). However, the most abundant norditerpenoid alkaloids in most D. barbeyi populations are either deltaline or 14-O-acetyldictyocarpine (14-OAD), which are both less toxic MDL-type alkaloids. Although the toxicities of MLA, 14-OAD, and deltaline have been individually determined, it is not known what impact, additive or antagonistic, large concentrations of deltaline or 14-OAD in the plant have on the toxicity of MLA. Consequently the focus of this study was to evaluate the effect of MDL-type alkaloids on the toxicity of MLA by comparing the LD50 and toxicokinetic profiles of these alkaloids administered individually to mice versus the co-administration of these alkaloids at three different ratios, 1:1, 1:5, and 1:25, MLA to individual MDL-type alkaloids. The LD50 for MLA alone was 4.4 ± 0.7 mg/kg BW, whereas the co-administration of MLA and deltaline at 1:1, 1:5, and 1:25 resulted in an LD50 of 2.7, 2.5, and 1.9 mg/kg BW, respectively. Similarly, the co-administration of MLA and 14-OAD at 1:1, 1:5, and 1:25 resulted in an LD50 of 3.1, 2.2, and 1.5 mg/kg BW, respectively. The increased toxicity of the mixtures did not result from increased MLA bioavailability or alterations in clearance of MLA from brain and muscle. These results suggest that MDL-type alkaloids have an additive effect on the toxicity of MLA in mice and may play a role in the overall toxicity of tall larkspur plants in cattle.