Novel Strategies Enhancing Bioavailability and Therapeutical Potential of Silibinin for Treatment of Liver Disorders

Abstract

Silibinin, a bioactive component found in milk thistle extract (Silybum marianum), is known to have significant therapeutic potential in the treatment of various liver diseases. It is considered a key element of silymarin, which is traditionally used to support liver function. The main mechanisms of action of silibinin are attributed to its antioxidant properties protecting liver cells from damage caused by free radicals. Experimental studies conducted in vitro and in vivo have confirmed its ability to inhibit inflammatory and fibrotic processes, as well as promote the regeneration of damaged liver tissue. Therefore, silibinin represents a promising tool for the treatment of liver diseases. Since the silibinin molecule is insoluble in water and has poor bioavailability in vivo, new perspectives on solving this problem are being sought. The two most promising approaches are the water-soluble derivative silibinin-C-2',3-dihydrogen succinate, disodium salt, and the silibinin-phosphatidylcholine complex. Both drugs are currently under evaluation in liver disease clinical trials. Nevertheless, the mechanism underlying silibinin biological activity is still elusive and its more detailed understanding would undoubtedly increase its potential in the development of effective therapeutic strategies against liver diseases. This review is focused on the therapeutic potential of silibinin and its derivates, approaches to increase the bioavailability and the benefits in the treatment of liver diseases that have been achieved so far. The review discusses the relevant in vitro and in vivo studies that investigated the protective effects of silibinin in various forms of liver damage.

Keywords: bioavailability; liver disease; silibinin-C-2‘3-dihydrogen succinate; silibinin-phosphatidylcholine complex; silybin.

Graphical abstract

Figure 1

The main flavonolignans and one flavonoid (taxifolin) of silymarin - an extract from the seeds of Milk thistle (Silybum marianum). Structure of molecules were drawn using ACD/ChemSketch software based on data from the PubChem database.

Figure 2

Wave spectrum of pure silibinin (Merck) with a maximum peak 289 nm (Our unpublished data).

Figure 3

Bioavailability of silibinin in different organs and plasma after a single oral application of pure silibinin at a dose of 50 mg/kg body weight in rodents. Levels of total silibinin was measured by HPLC or LC-MS method. Data were obtained from published levels of silibinin in the tissues and plasma, and represent mean ± SD.,

Figure 4

Level of total (A) and unconjugated (B) silibinin in rat plasma after a single oral application of Silipide (200 mg/kg) or pure silibinin (50, 200, or 500 mg/kg). Data were obtained from published levels of total and unconjugated silibinin in plasma, and represent mean ± SD.,,

Figure 5

The number of publications since 2000, according to the PubMed database, in which the word silymarin, silibinin, or taxifolin is mentioned. On average, there have been almost 200 new publications with silymarin, 100 with silibinin, and 50 with taxifolin per year since 2000. However, since 2014, the number of new publications has increased significantly, with an average of almost 280 new publications with silymarin, 140 with silibinin, and 80 with taxifolin being published annually.

Figure 6

The cell viability/reduction rate of MTT dye after 24 hours of exposure to silibinin in cancerous HepG2 (A), Huh7 (B), Hep3B (C) or noncancerous AML12, FL83B (D), LX-2 (F), human (A–C, F) or animal (D) cell lines or primary animal hepatocytes (E). The gray lines represent the measurements from the values published in articles. The red line represents the Lorentzian (Cauchy) model of nonlinear regression from grey lines with a 95% confidence level. Citations for selected cell lines and time point 24h are available in Table 1.

Figure 7

The total dose of silibinin was calculated as a single dose of silibinin multiplied by number of administrations as given in respective publications. Each dot represents one in vivo experiment with silibinin, the grey dot represents pure silibinin, the green dot corresponds to water-soluble silibinin, the red dot represents the combination with phospholipids, the blue dot represents silibinin nanoparticles, and the yellow dot represents other combinations (with vitamin E, Puert tea or collagenase I). The lines represent mean ± SEM. All publications are mentioned in Table 2. Shapiro–Wilk normality test was used to test distribution. Statistical differences are calculated by unpaired t-test with Welch’s correction. The original findings and relevant citations are described in Table 2 and Supplementary Table 1.

Figure 8

Effect of pure silibinin (grey dot) and modified silibinin (green dot: water-soluble silibinin; red dot: combination with phospholipids; blue dot: silibinin nanoparticles; yellow dot: the combination with other supplements) on the serum level of ALT and AST according to the published data. The values are expressed as the ratio of the treated to the untreated diseased animal (A and B). 100% - animal model of disease; 0% - healthy animal. Efficacy is expressed as the ratio of ALT or AST to the total administered dose of silibinin, normalized to per os pure silibinin as the smallest changes were detected compared to other routes of administration (C and D). Shapiro–Wilk normality test was used to test distribution. Statistical differences were calculated by Welch and Brown-Forsythe one-way ANOVA with Dunnett correction. *(p<0.05), **(p<0.01), ***(p<0.001), ****(p<0.0001). The original findings and relevant citations are described in Table 2 and Supplementary Table 1.