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Concept: Flavonolignan


Organic anion-transporting polypeptides (OATPs) are multispecific transporters mediating the uptake of endogenous compounds and xenobiotics in tissues that are important for drug absorption and elimination, including the intestine and liver. Silymarin is a popular herbal supplement often used by patients with chronic liver disease; higher oral doses than those customarily used (140 mg three times/day) are being evaluated clinically. The present study examined the effect of silymarin flavonolignans on OATP1B1-, OATP1B3-, and OATP2B1-mediated transport in cell lines stably expressing these transporters, and in human hepatocytes. In overexpressing cell lines, OATP1B1- and OATP1B3-mediated estradiol-17β-glucuronide uptake and OATP2B1-mediated estrone-3-sulfate uptake were inhibited by most of the silymarin flavonolignans investigated. OATP1B1-, OATP1B3-, and OATP2B1-mediated substrate transport was inhibited efficiently by silymarin (IC(50) values of 1.3, 2.2 and 0.3 μM, respectively), silybin A (IC(50) values of 9.7, 2.7 and 4.5 μM, respectively), silybin B (IC(50) values of 8.5, 5.0 and 0.8 μM, respectively), and silychristin (IC(50) values of 9.0, 36.4 and 3.6 μM, respectively). Furthermore, silymarin, silybin A and silybin B (100 μM) significantly inhibited OATP-mediated estradiol-17β-glucuronide and rosuvastatin uptake into human hepatocytes. Calculation of the maximal unbound portal vein concentrations/IC(50) values indicated a low risk for silymarin-drug interactions in hepatic uptake with a customary silymarin dose. The extent of silymarin-drug interactions depends on OATP isoform specificity and concentrations of flavonolignans at the site of drug transport. Clinical investigations that achieve higher concentrations with either increased doses of silymarin or formulations with improved bioavailability may enhance the potential risk of DDIs with OATP substrates.

Concepts: Pharmacology, Liver, Glycogen, Bile, Transport, Hepatocyte, Flavonolignan, Silibinin


MMilk thistle (Silybum marianum) extracts, one of the most widely used dietary supplements, contain a mixture of six major flavonolignans (silybin A, silybin B, isosilybin B, isosilybin A, silychristin, and silydianin) and other components. However, the pharmacokinetics of the free individual flavonolignans has only partially been investigated in humans. Further, antioxidant effects of the extract, which may underlie the basis of many therapeutic effects, have not been thoroughly assessed. The present study was to evaluate the pharmacokinetics of the six major flavonolignans in healthy volunteers receiving single doses either one(175 mg), two(350 mg), or three(525 mg) of milk thistle capsule(s) on three separate study visits. Additionally, the steady state pharmacokinetic parameters were determined after the subjects were administered one capsule thrice daily for 28 consecutive days. Our results demonstrated that all six flavonolignans were rapidly absorbed and eliminated. In order of abundance, the exposure to free flavonolignans was greatest for silybin A followed by silybin B, isosilybin B, isosilybin A, silychristin, and silydianin. The systemic exposure to these compounds appeared linear and dose-proportional. The disposition of flavonolignans was stereoselective, as evidenced by the apparent clearance of silybin B, which was significantly greater than silybin A, whereas the apparent clearance of isosilybin B was significantly lower than isosilybin A. The concentrations of urinary 8-epi-prostaglandin F2α, a commonly used biomarker of oxidative status in humans, were considerably decreased in study subjects after a 28-day exposure to the extract (1.3±0.9 versus 0.8±0.9 ng/mg creatinine), but failed to reach statistical significance (P=0.076).

Concepts: Therapeutic effect, Antioxidant, Pharmacokinetics, Silybum marianum, Milk thistle, Flavonolignan, Silibinin, Amanita phalloides


Silymarin, a standardized extract of the seeds of the milk thistle (Silybum marianum) and its major component, silybin, is now used as an active component in a broad spectrum of dietary supplements, cosmetics and dermatological preparations. However, despite its use in skin products, there are no published data to exclude its phototoxic potential. The primary purpose of this study was to examine the phototoxicity of silymarin and its flavonolignans, silybin, isosilybin, silychristin, silydianin and 2,3-dehydrosilybin by validated 3T3 NRU assay. Further, we compared the validated biological system Balc/c 3T3 cell line with other cell models, particularly normal human dermal fibroblasts (NHDF), normal human epidermal keratinocytes (NHEK) and the human keratinocyte cell line (HaCaT). The results showed that silymarin and the flavonolignans silybin, isosilybin, silychristin and silydianin had no phototoxicity towards any of the cells used. In contrast, 2,3-dehydrosilybin was identified as a compound with phototoxic potential. Further study is needed to evaluate the health risks associated with 2,3-dehydrosilybin use in skin preparations.

Concepts: Fibroblast, Epidermis, Keratinocyte, Silybum marianum, Milk thistle, Flavonolignan, Silibinin, Amanita phalloides


The protective constituents of silymarin, an extract from Silybum marianum fruits, have been extensively studied in terms of their antioxidant and hepatoprotective activities. Here, we explore the electron-donor properties of the major silymarin flavonolignans. Silybin (SB), silychristin (SCH), silydianin (SD) and their respective 2,3-dehydroderivatives (DHSB, DHSCH and DHSD) were oxidized electrochemically and their antiradical/antioxidant properties were investigated. Namely, Folin-Ciocalteau reduction, DPPH and ABTS(+) radical scavenging, inhibition of microsomal lipid peroxidation and cytoprotective effects against tert-butyl hydroperoxide-induced damage to a human hepatocellular carcinoma HepG2 cell line were evaluated. Due to the presence of the highly reactive C3-OH group and the C-2,3 double bond (ring C) allowing electron delocalization across the whole structure in the 2,3-dehydroderivatives, these compounds are much more easily oxidized than the corresponding flavonolignans SB, SCH and SD. This finding was unequivocally confirmed not only by experimental approaches, but also by density functional theory (DFT) calculations. The hierarchy in terms of ability to undergo electrochemical oxidation (DHSCH~DHSD>DHSB»SCH/SD>SB) was consistent with their antiradical activities, mainly DPPH scavenging, as well as in vitro cytoprotection of HepG2 cells. The results are discussed in the context of the antioxidant vs. prooxidant activities of flavonolignans and molecular interactions in complex biological systems.

Concepts: Antioxidant, Redox, Electrochemistry, Density functional theory, Vitamin C, Silybum marianum, Flavonolignan, Silibinin


Silymarin is a hepatoprotective mixture of flavonolignans and flavonoids extracted from the seeds of milk thistle (Silybum marianum L. Gaertn). This study investigates the effect of major bioactive constituents from silymarin, silybin A, silybin B, isosilybin A, isosilybin B, silydianin, silychristin, isosilychristin, and taxifolin, on the expression of ABCA1, an important cholesterol efflux transporter, in THP-1-derived macrophages. Four of the studied compounds, isosilybin A, silybin B, silychristin and isosilychristin, were found to significantly induce ABCA1 protein expression without affecting cell viability. Moreover, isosilybin A, a partial PPARγ agonist, was found to promote cholesterol efflux from THP-1 macrophages in a concentration-dependent manner. These findings first show ABCA1 protein up-regulating activity of active constituents of silymarin and provide new avenues for their further study in the context of cardiovascular disease.

Concepts: Nutrition, Atherosclerosis, Silybum marianum, Milk thistle, Flavonolignan, Silibinin, Silybum, Amanita phalloides


A series of neuroprotective hybrid compounds was synthesized by conjugation of the flavonolignan silibinin with natural phenolic acids, such as ferulic, cinnamic and syringic acid. Selective 7-O-esterfication without protection groups was achieved by applying the respective acyl chlorides. Sixteen compounds were obtained and SARs were established by evaluating antioxidative properties in the physicochemical FRAP assay, as well as in a cell-based neuroprotection assay using murine hippocampal HT-22 cells. Despite weak activities in the FRAP assay, esters of the α,β-unsaturated acids showed pronounced overadditive effects at low concentrations greatly exceeding the effects of equimolar mixtures of silibinin and the respective acids in the neuroprotection assay. Cinnamic and ferulic acid esters (5a and 6a) also showed overadditive effects regarding inhibition of microglial activation, PC12 cell differentiation, in vitro ischemia as well as anti-aggregating abilities against Aβ42 peptide and τ protein. Remarkably, the esters of ferulic acid with silybin A and silybin B (11a and 11b) showed a moderate but significant difference in both neuroprotection and in their anti-aggregating capacities. The results demonstrate that non-toxic natural antioxidants can be regioselectively connected as esters with medium-term stability exhibiting very pronounced overadditive effects in a portfolio of biological assays.

Concepts: Protein, Antioxidant, Carbonyl, Phenols, Neuroprotection, Antioxidants, Flavonolignan, Silibinin


Milk thistle (Silybum marianum) is a medicinal plant that has been used for thousands of years as a remedy for a variety of ailments. The main component of S. marianum fruit extract (silymarin) is a flavonolignan called silybin, which is not only the major silymarin element but is also the most active ingredient of this extract, which has been confirmed in various studies. This compound belongs to the flavonoid group known as flavonolignans. Silybin’s structure consists in two main units. The first is based on a taxifolin, the second a phenyllpropanoid unit, which in this case is conyferil alcohol. These two units are linked together into one structure by an oxeran ring. Since the 1970s, silybin has been regarded in official medicine as a substance with hepatoprotective properties. There is a large body of research that demonstrates silybin’s many other healthy properties, but there are still a lack of papers focused on its molecular structure, chemistry, metabolism, and novel form of administration. Therefore, the aim of this paper is a literature review presenting and systematizing our knowledge of the silybin molecule, with particular emphasis on its structure, chemistry, bioavailability, and metabolism.

Concepts: Molecule, Chemical substance, Silybum marianum, Milk thistle, Flavonolignan, Silibinin, Silybum, Amanita phalloides


The extract from milk thistle (Silybum marianum (L.) Gaertn. (Asteraceae)), known as silymarin, contains a variety of flavonolignans and displays antioxidant, anti-inflammatory, immunomodulatory and hepatoprotective properties. As silybin is the main component of silymarin, the literature mainly focuses on this compound, ignoring all other components. This leads to problems in reproducibility of scientific results, as the exact composition of silymarin is often unknown and can vary to a certain degree depending on the processing, chemo-variety of the plant used and climatic conditions during the plant growth. There are studies dealing with the analytical separation and quantification of silymarin components as well as studies focused on silymarin content in clinically used drugs, in various plant parts, seasons, geographic locations etc. However, no comparison of detail flavonolignan profiles in various silymarin preparations is available to date. Also, as a result of the focus on the flavonolignans; the oil fraction, which contains linoleic, oleic and palmitic acids, sterols, tocopherol (vitamin E) and phospholipids, has been neglected. Due to all these factors, the whole plant is used e.g. as animal feed, the leaves can be eaten in salads and seed oil, besides culinary uses, can be also utilized for biodiesel or polymer production. Various HPLC separation techniques for the determination of the content of the flavonolignans have been vastly summarized in the present review.

Concepts: Antioxidant, Palm oil, Silybum marianum, Milk thistle, Flavonolignan, Silibinin, Amanita phalloides, Flavonolignans


Silymarin is a collection of compounds extracted from the medicinal herb milk thistle, among which silybin is the major flavonolignan. However, the biosynthesis pathway of silybin remains unclear. In this study, biomimetic reactions demonstrated that silybin can be synthesized from coniferyl alcohol and taxifolin by the action of peroxidase. The concentration profiles of silybin and its precursors and RNA-Seq analysis of gene expression revealed that the amount of taxifolin and the activity of peroxidase serve as the limiting factors in silybin biosynthesis. Hierarchical clustering of the expression profile of genes of the flavonoid biosynthesis pathway distinguished flowers from other organs. RNA-Seq revealed five candidates for the peroxidase involved in silybin production, among which APX1 (ascorbate peroxidase1) showed a distinct peroxidase activity and the capacity to synthesize silybin. The spatial organization of silybin biosynthesis in milk thistle was elucidated, which could help our understanding of the biosynthesis of silybin and other flavonolignans. This article is protected by copyright. All rights reserved.

Concepts: DNA, Gene, Gene expression, Silybum marianum, Milk thistle, Flavonolignan, Silibinin, Flavonolignans


Silymarin is the phytochemical with medicinal properties extracted from Silybum marianum (L.) Gaertn. fruits. Yet, little information is available about silymarin biosynthesis. Moreover, the generally accepted pathway, formulated thus far, is not in agreement with actual experimental measurements on flavonolignan contents. The present work analyses flavonolignan and taxifolin content in 201 S. marianum samples taking into consideration a wide phenotypic variability. Two stable chemotypes were identified: one characterized by both high silychristin and silybin content (chemotype A) and another by a high silydianin content (chemotype B). Through the correlation analysis of samples divided according to chemotype, it was possible to construct a simplified silymarin biosynthetic pathway that is sufficiently versatile in explaining experimental results responding to the actually unresolved questions about this process. The proposed pathway highlights that three separate and equally sized metabolite pools exist, namely: diastereoisomers A (silybin A plus isosilybin A), diastereoisomers B (silybin B plus isosilybin B) and silychristin. In both A and B diastereoisomers pools, isosilybin A and isosilybin B always represent a given amount of the metabolite flux through the specific metabolite pool suggesting the possible involvement of dirigent protein-like enzymes. We suggest that chemotype B possesses a complete silymarin biosynthetic pathway in which silydianin biosynthesis is enzymatically controlled. On the contrary, chemotype A is probably a natural mutant unable to biosynthesize silydianin. The present simplified pathway for silymarin biosynthesis will constitute an important tool for the further understanding of the reactions that drive flavonolignan biosynthesis in S. marianum.

Concepts: Amino acid, Metabolism, Adenosine triphosphate, Enzyme, Silybum marianum, Flavonolignan, Silibinin, Amanita phalloides