Silymarin dehydroflavonolignans chelate zinc and partially inhibit alcohol dehydrogenase

0550096 - MBÚ 2022 RIV CH eng J - Článek v odborném periodiku
Tvrdý, V. - Hrubša, M. - Jirkovský, E. - Biedermann, David - Kutý, M. - Valentová, Kateřina - Křen, Vladimír - Mladěnka, P.
Silymarin dehydroflavonolignans chelate zinc and partially inhibit alcohol dehydrogenase.
Nutrients. Roč. 13, č. 12 (2021), č. článku 4238. E-ISSN 2072-6643
Grant CEP: GA ČR(CZ) GA18-00121S
Institucionální podpora: RVO:61388971
Klíčová slova: Alcohol dehydrogenase * Chelation * Dehydrosilybin * Docking * Flavonolignans * Glutamate dehydrogenase * Silybin * Zinc
Obor OECD: Biochemistry and molecular biology
Impakt faktor: 6.706, rok: 2021
Způsob publikování: Open access
https://www.mdpi.com/2072-6643/13/12/4238

Silymarin is known for its hepatoprotective effects. Although there is solid evidence for its protective effects against Amanita phalloides intoxication, only inconclusive data are available for alcoholic liver damage. Since silymarin flavonolignans have metal-chelating activity, we hypothesized that silymarin may affect alcoholic liver damage by inhibiting zinc-containing alcohol dehydrogenase (ADH). Therefore, we tested the zinc-chelating activity of pure silymarin flavonolignans and their effect on yeast and equine ADH. The most active compounds were also tested on bovine glutamate dehydrogenase, an enzyme blocked by zinc ions. Of the six flavonolignans tested, only 2,3-dehydroderivatives (2,3-dehydrosilybin and 2,3- dehydrosilychristin) significantly chelated zinc ions. Their effect on yeast ADH was modest but stronger than that of the clinically used ADH inhibitor fomepizole. In contrast, fomepizole strongly blocked mammalian (equine) ADH. 2,3-Dehydrosilybin at low micromolar concentrations also partially inhibited this enzyme. These results were confirmed by in silico docking of active dehydroflavonolignans with equine ADH. Glutamate dehydrogenase activity was decreased by zinc ions in a concentration-dependent manner, and this inhibition was abolished by a standard zinc chelating agent. In contrast, 2,3-dehydroflavonolignans blocked the enzyme both in the absence and presence of zinc ions. Therefore, 2,3-dehydrosilybin might have a biologically relevant inhibitory effect on ADH and glutamate dehydrogenase.
Trvalý link: http://hdl.handle.net/11104/0325947