Antioxidant, Anti-Inflammatory, and Multidrug Resistance Modulation Activity of Silychristin Derivatives.

Jitka Viktorová,Karolína Šeborová,Radka Václavíková,Kateřina Řehořová,Kateřina Valentová,David Biedermann,Simona Dobiasová,Tomáš Macek,Vladimír Křen,Kristýna Káňová,Tomáš Ruml

doi:10.3390/antiox8080303

Abstract

Silychristin A is the second most abundant compound of silymarin. Silymarin complex was previously described as an antioxidant with multidrug resistance modulation activity. Here, the results of a classical biochemical antioxidant assay (ORAC) were compared with a cellular assay evaluating the antioxidant capacity of pure silychristin A and its derivatives (anhydrosilychristin, isosilychristin and 2,3-dehydrosilychristin A). All the tested compounds acted as antioxidants within the cells, but 2,3-dehydro- and anhydro derivatives were almost twice as potent as the other tested compounds. Similar results were obtained in LPS-stimulated macrophages, where 2,3-dehydro- and anhydrosilychristin inhibited NO production nearly twice as efficiently as silychristin A. The inhibition of P-glycoprotein (P-gp) was determined in vitro, and the respective sensitization of doxorubicin-resistant ovarian carcinoma overproducing P-gp was detected. Despite the fact that the inhibition of P-gp was demonstrated in a concentration-dependent manner for each tested compound, the sensitization of the resistant cell line was observed predominantly for silychristin A and 2,3-dehydrosilychristin A. However, anhydrosilychristin and isosilychristin affected the expression of both the P-gp (ABCB1) and ABCG2 genes. This is the first report showing that silychristin A and its 2,3-dehydro-derivative modulate multidrug resistance by the direct inhibition of P-gp, in contrast to anhydrosilychristin and isosilychristin modulating multidrug resistance by downregulating the expression of the dominant transmembrane efflux pumps.

Highlights

Silychristin is the second most abundant flavonolignan in the silymarin complex, which is usually produced by the acetone extraction of Silybum marianum (L.) Gaertn. fruits [1].Despite its high content in the silymarin complex and its biological potential, little attention has been paid to this compound, mainly due to its rather difficult separation leads to its co-elution with one of its isomeric flavonolignans, silydianin [1], a problem that has been resolved recently [2]by careful chromatography on LH-20 gel
We describe the ability of silychristin and its 2,3-dehydro- derivative to inhibit P-glycoprotein (P-gp) and reverse the doxorubicin-resistance phenotype in resistant human ovarian carcinoma. In contrast to this direct inhibition of P-gp, we suggest that anhydrosilychristin and isosilychristin modulates the multidrug resistance by downregulating the expression of the dominant transmembrane efflux pumps
Silychristin A and its derivatives were compared for their antioxidant capacity by the classical chemical method (ORAC) and by measurement of their radical scavenging activity inside the cells (CAA)

Summary

Introduction

Silychristin is the second most abundant flavonolignan in the silymarin complex, which is usually produced by the acetone extraction of Silybum marianum (L.) Gaertn. (milk thistle) fruits [1].Despite its high content in the silymarin complex and its biological potential, little attention has been paid to this compound, mainly due to its rather difficult separation leads to its co-elution with one of its isomeric flavonolignans, silydianin [1], a problem that has been resolved recently [2]by careful chromatography on LH-20 gel. Silychristin is the second most abundant flavonolignan in the silymarin complex, which is usually produced by the acetone extraction of Silybum marianum (L.) Gaertn. Despite its high content in the silymarin complex and its biological potential, little attention has been paid to this compound, mainly due to its rather difficult separation leads to its co-elution with one of its isomeric flavonolignans, silydianin [1], a problem that has been resolved recently [2]. As other components of the silymarin complex, silychristin has antioxidant properties. Its potential to scavenge the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical is nearly 14× higher than that of silybin (considered “the active component of silymarin”) and approximately 1.5× lower than that of its oxidized derivative 2,3-dehydrosilybin [5,6].

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