Substituent Effects in the Free Radical Reactions of Silybin: Radiation-induced Oxidation of the Flavonoid at Neutral pH

Abstract

Silybin dihemisuccinate sodium salt, a flavonoid used in human therapy of liver dysfunction, has an inhibitory effect in vivo on radiation-induced deactivation of enzymes and peroxidation of membrane lipids in rat liver microsomes. The reactivity of silybin and its phenolic OH groups towards free radicals in aqueous solution was studied by pulse radiolysis. Absorption spectra for the phenoxyl-type radicals were assigned using structurally similar models. The one-electron reduction potential for silybin at pH 7 (E⁰₇ = 0·76 V), determined using the p-methoxy-phenoxyl/phenolate redox couple as reference standard (E⁰₇ = 0·72 V, Lind et al. 1990), is related to the 3′-methoxy-4′-OH structure, the exclusive target for one-electron oxidation at pH7, while the 7-OH and 5-OH groups are prevented from oxidation by 4-keto substitution and intramolecular H-bonding, respectively. The free radical reactivity of silybin compares favourably with poly-OH-substituted flavonoids; however, the latter compounds have been reported to generate potentially toxic oxygen species at a biologically relevant pH.