Direct and indirect targets of carboxyatractyloside, including overlooked toxicity toward nucleoside diphosphate kinase (NDPK) and mitochondrial H⁺ leak

Abstract

Context

The toxicity of atractyloside/carboxyatractyloside is generally well recognized and commonly ascribed to the inhibition of mitochondrial ADP/ATP carriers, which are pivotal for oxidative phosphorylation. However, these glycosides may 'paralyze' additional target proteins.

Objective

This review presents many facts about atractyloside/carboxyatractyloside and their plant producers, such as Xanthium spp. (Asteraceae), named cockleburs.

Methods

Published studies and other information were obtained from databases, such as 'CABI - Invasive Species Compendium', 'PubMed', and 'The World Checklist of Vascular Plants', from 1957 to December 2022. The following major keywords were used: 'carboxyatractyloside', 'cockleburs', 'hepatotoxicity', 'mitochondria', 'nephrotoxicity', and 'Xanthium'.

Results

In the third decade of the twenty first century, public awareness of the severe toxicity of cockleburs is still limited. Such toxicity is often only perceived by specialists in Europe and other continents. Interestingly, cocklebur is among the most widely distributed invasive plants worldwide, and the recognition of new European stands of Xanthium spp. is provided here. The findings arising from field and laboratory research conducted by the author revealed that (i) some livestock populations may instinctively avoid eating cocklebur while grazing, (ii) carboxyatractyloside inhibits ADP/GDP metabolism, and (iii) the direct/indirect target proteins of carboxyatractyloside are ambiguous.

Conclusions

Many aspects of the Xanthium genus still require substantial investigation/revision in the future, such as the unification of the Latin nomenclature of currently distinguished species, bur morphology status, true fruit (achene) description and biogeography of cockleburs, and a detailed description of the physiological roles of atractyloside/carboxyatractyloside and the toxicity of these glycosides, mainly toward mammals. Therefore, a more careful interpretation of atractyloside/carboxyatractyloside data, including laboratory tests using Xanthium-derived extracts and purified toxins, is needed.

Keywords:

• ADP/ATP carrier (AAC)
• atractyloside
• cattle
• cockleburs
• hepatotoxicity
• mitochondria
• nephrotoxicity
• oxidative phosphorylation
• Traditional Chinese Medicine
• uncoupling protein (UCP)

Acknowledgments

I am grateful to Prof. Maria Wojterska from Adam Mickiewicz University in Poznan (Faculty of Biology, Department of Plant Ecology and Environmental Protection), who authenticated the identity of representatives of the Xanthium genus.

Author contributions

Andrzej M. Woyda-Ploszczyca raised funds, conceived the review, wrote the paper, took the photos and created the table and figures.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by grant [2015/19/D/NZ3/00087] from the National Science Center, Poland (Principal Investigator: Dr. hab. Andrzej M. Woyda-Ploszczyca). The sponsor had no involvement in preparing the article or the decision to submit the article for publication.