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This Article Full Text (PDF) All Versions of this Article: jas.2008-1025v1 86/10/2761    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Welch, K. D. Articles by Stegelmeier, B. L. Search for Related Content PubMed PubMed Citation Articles by Welch, K. D. Articles by Stegelmeier, B. L.

The effect of 7, 8-methylenedioxylycoctonine-type diterpenoid alkaloids on the toxicity of methyllycaconitine in mice

USDA-ARS Poisonous Plant Research Laboratory, Logan, Utah 84341

Kevin.Welch{at}ars.usda.gov

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). Toxicity of many tall larkspurs such as Delphinium barbeyi has been attributed to its high concentration of MSAL-type alkaloids including methyllycaconitine (MLA). However, the norditerpenoid alkaloids found in highest concentrations in most D. barbeyi populations are either deltaline or 14-O-acetyldictyocarpine (14-OAD), both less toxic MDL-type alkaloids. Although the individual toxicities of MLA, 14-OAD, and deltaline have been determined, the impact (additive or antagonistic) that large concentrations of deltaline or 14-OAD in the plant have on the toxicity of MLA is unknown. Consequently the effect of MDL-type alkaloids on the toxicity of MLA were compared using LD₅₀ and toxicokinetic profiles of brain and muscle from mice receiving i.v. administration of these alkaloids individually or in combination at ratios of: 1:1, 1:5, and 1:25, MLA : 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. Co-administration of mixtures did not result in increased MLA bioavailability or alterations in clearance from brain and muscle. Consequently, the increased toxicity of the mixtures was not a result of increased MLA bioavailability (based on maximum concentrations observed) or alterations in MLA clearance from brain and muscle, as these were unchanged. These results demonstrate that MDL-type alkaloids have an additive effect on MLA toxicity in mice, and may also play a role in the overall toxicity of tall larkspur plants in cattle.

Key Words: Delphinium • diterpenoid alkaloids • larkspur • LD₅₀ • methyllycaconitine