Dual effect of silymarin on experimental non-alcoholic steatohepatitis induced by irinotecan

Abstract

Irinotecan-based regimens are commonly used for treatment of colorectal cancer, which is limited by mucositis and non-alcoholic steatohepatitis (NASH). Silymarin (SIL) prevents fatty liver disease in the clinical setting and in models of liver damage induced chemically. This study investigated the possible effect of SIL on irinotecan (IRI)-induced NASH. Swiss female mice were injected with saline (SAL 5ml/kg i.p.), IRI (50mg/kg i.p.), SIL (150mg/kg p.o.) or IRI (50mg/kg i.p.)+(SIL 1.5, 15 or 150mg/kg p.o.) thrice/week/7weeks. On the seventh week, blood samples were collected for transaminases assay and livers were collected for histopathology, measurement of the total lipids, malondyadehyde (MDA), non-protein sulfhydryl groups (NPSH), cytokines (IL-1β, IL 6 and IL-10), 3-nitrotyrosine (N-Tyr) and toll-like receptor 4 (TLR4) immunoexpression, quantification of NF-kB, α-smooth muscle actin (α-SMA), and Escherichia coli 16S rRNA gene (RRS) expression. IRI increased liver transaminases, neutrophil infiltration, lipid accumulation, MDA, IL-1β and IL-6 levels, N-Tyr and TLR4 immunostaining, NF-kB, α-SMA expression and RRS versus the SAL group (p<0.05). Additionally, SIL (1.5mg/kg) improved these parameters (p<0.05), except neutrophil infiltration and RSS versus the IRI group. Furthermore, the SIL (15mg/kg) only improved the inflammatory parameters, the expression of α-SMA and RRS versus the IRI group (p<0.05). The higher dose of SIL (150mg/kg) was even more deleterious than the intermediate dose. Therefore, silymarin showed a dual effect on liver damage induced by IRI. Hepatoprotection seems to involve the inhibition of oxidative stress and protein nitrosylation, preventing activation of hepatic fibrosis mechanisms.

Nonalcoholic Fatty Liver Disease: Pathogenesis and Treatment in Traditional Chinese Medicine and Western Medicine

“…It is effective in the treatment of obesity-related NASH [163], prevents the establishment of alcoholic steatohepatitis [165] and silymarin pretreatment reduced the accumulation of fat in the liver of mice that received irinotecan. is supports the assumption that lipid accumulation occurs due to mitochondrial dysfunction [167]. Low doses of silymarin prevent the appearance of clinical signs highly correlated to NASH [168,169] such as lobular inflammation, steatosis, and vacuolation and also prevent the expression of α-smooth muscle actin, a known fibrosis marker associated with advanced NASH.…”

“…Schrieber et al showed that the disposition of silymarin, an herbal medicine widely used by patients with liver disease, is significantly altered in patients with liver disease [162]. Silymarin hepatic protection has been widely demonstrated in animal models and in clinical setting [163][164][165][166][167][168]. It is effective in the treatment of obesity-related NASH [163], prevents the establishment of alcoholic steatohepatitis [165] and silymarin pretreatment reduced the accumulation of fat in the liver of mice that received irinotecan.…”

Irinotecan and Δ9-Tetrahydrocannabinol Interactions in Rat Liver: A Preliminary Evaluation Using Biochemical and Genotoxicity Markers

“…Not many rodent studies up to now evaluated the same biomarkers of liver function after exposure to IRI, but they reported generally similar results [ 36 , 81 , 82 , 83 ]. The existing literature on serum markers of rodent hepatocellular damage after exposure to THC is inconsistent [ 38 , 39 , 40 , 41 , 63 , 64 , 84 ].…”

Potential Therapeutic Benefits of Herbs and Supplements in Patients with NAFLD

“…Silymarin is the extract from the milk thistle plant ( Silybum marianum ); both Silybum and silymarin have been consistently studied with respect to NAFLD and have been shown to have therapeutic effects [ 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 ]. Silymarin has been used for centuries as a natural remedy for liver disease [ 10 ].…”

“…Silymarin is also able to reduce hepatic inflammation through activation of the farnesyl X receptor (FXR) which correlates with the inhibition of NF-κB transactivity [ 12 , 16 ]. Due to the vast data supporting milk thistle as a therapeutic option from experimental mouse studies, there are multiple clinical trials testing its effects [ 7 , 9 , 11 , 12 , 16 , 17 , 18 , 20 , 21 , 22 ]. In a randomized double-blinded, placebo-controlled trial, Wah Kheong et al tested the effects of silymarin supplementation on adult patients with biopsy-proven NASH and a NAFLD activity score (NAS) of greater than 4 [ 23 ].…”