Chapter 14 - Silymarin Flavonolignans: Structure–Activity Relationship and Biosynthesis

Abstract

Silymarin is a well-known hepatoprotective agent having an exceptional safety profile. It exerts its action by antioxidant, anti-inflammatory, immunomodulatory, antiproliferative, antifibrotic, and antiviral activities. Silymarin is composed of an isomeric mixture of seven flavonolignans silybin A, silybin B, isosilybin A, isosilybin B, silychristin A, silychristin B, and silydianin and one flavonoid taxifolin. Silibinin, a mixture of silybin A and silybin B, is considered responsible for the hepatoprotective functions of silymarin. Purification of these compounds in gram scale allowed for testing the hepatoprotective effects of pure compounds in various assays. Some individual flavonolignans showed stronger hepatoprotective functions than silymarin. Only isosilybin B showed high toxicity to human hepatoma cell line. Isosilybin A, taxifolin, and silibinin were the most effective hepatoprotectors. Isosilybin B showed the highest antiproliferative activity against human prostate carcinoma cell lines. Biosynthesis of silymarin flavonolignans occurs by oxidative coupling between the phenylpropanoid coniferyl alcohol and the flavonoid taxifolin. Flavonoid biosynthesis involves phenylpropanoid and polyketide pathways. Plant tissue culture studies have largely contributed to our current understanding of silymarin biosynthesis. Production of silymarin in Silybum marianum cultures can be stimulated by treatment with elicitors such as yeast extract and methyl jasmonate. The components of phenylpropanoid pathway are not modified by elicitation of cell cultures of S. marianum with yeast extract or methyl jasmonate. This was concluded when the overall metabolic changes in elicitor-treated cultures were studied using nuclear magnetic spectroscopy. The flavonoid biosynthesis, not coniferyl alcohol biosynthesis, may be the candidate component of the signaling pathway involved in stimulation of flavonolignan biosynthesis with elicitors. Understanding the basic signaling components in the transduction of the elicitor signal to downstream responses such as silymarin production is mandatory for biotechnological exploitation of this valuable pharmaceutical raw material. Lipoxygenase involvement in the elicitor-induced accumulation of silymarin is well established. Inhibition of external and internal calcium fluxes significantly increases flavonolignan production. Activation of phospholipase D after elicitor treatment mediates silymarin secretion into the culture medium, indicating possible involvement of the enzyme in deposition of silymarin in the external cover of the fruits of S . marianum .