Is hydroxypyridonate 3,4,3‐LI(1,2‐HOPO) a good competitor of fetuin for uranyl metabolism?


Is hydroxypyridonate 3,4,3‐LI(1,2‐HOPO) a good competitor of fetuin for uranyl metabolism?

Younes, A.; Creff, G.; Beccia, M. R.; Moisy, P.; Roques, J.; Aupiais, J.; Hennig, C.; Solari, P. L.; Den Auwer, C.; Vitaud, C.

Uranium is widespread in the environment, resulting both from natural occurrences and anthropogenic activities. Its toxicity is mainly chemical rather than radiological. In the blood it is transported as uranyl UO22+ cation and forms complexes with small ligands like carbonates and with some proteins. From there it reaches the skeleton, its main target organ for accumu lation. Fetuin is a serum protein involved in biomineralization processes which was demonstrated to be the main UO22+‐binder in vitro. Fetuin’s life cycle ends in bone. It is thus suspected to be a key protagonist of U accumulation in this organ. Up to now, there has been no effective treatment for the removal of U from the body and studies devoted to the interactions involving chelating agents with both UO22+ and its protein targets are lacking. The present work aims at studying the potential role of the 3,4,3‐LI(1,2‐HOPO) as a promising chelating agent in competition with fetuin. The apparent affinity constant of the 3,4,3‐LI(1,2‐HOPO) was first determined, giving evidence for its very high affinity similarity to that of fetuin. Chromatography experiments, aimed at identifying the complexes formed and quantify their UO22+ content, and spectroscopic structural investigations (XAS) were carried out, demonstrating that the 3,4,3‐LI(1,2‐HOPO) inhibits/limits the formation of fetuin‐uranyl complexes in stoichiometric conditions. But surprisingly, possible ternary complexes stable enough to remain present after the process, were identified for sub stoichiometric conditions of HOPO versus fetuin. These results contribute to the understanding of the mechanisms accounting for U residual accumulation despite the chelation therapy after internal contamination.

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Publ.-Id: 28389