Silymarin protects liver against toxic effects of anti-tuberculosis drugs in experimental animals

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Abstract

Background

The first line anti-tuberculosis drugs isoniazid (INH), rifampicin (RIF) and pyrazinamide (PZA) continues to be the effective drugs in the treatment of tuberculosis, however, the use of these drugs is associated with toxic reactions in tissues, particularly in the liver, leading to hepatitis. Silymarin, a standard plant extract with strong antioxidant activity obtained from S. marianum, is known to be an effective agent for liver protection and liver regeneration. The aim of this study was to investigate the protective actions of silymarin against hepatotoxicity caused by different combinations of anti-tuberculosis drugs.

Methods

Male Wistar albino rats weighing 250–300 g were used to form 6 study groups, each group consisting of 10 rats. Animals were treated with intra-peritoneal injection of isoniazid (50 mg/kg) and rifampicin (100 mg/kg); and intra-gastric administration of pyrazinamid (350 mg/kg) and silymarin (200 mg/kg). Hepatotoxicity was induced by a combination of drugs with INH+RIF and INH+RIF+PZA. Hepatoprotective effect of silymarin was investigated by co-administration of silymarin together with the drugs. Serum biochemical tests for liver functions and histopathological examination of livers were carried out to demonstrate the protection of liver against anti-tuberculosis drugs by silymarin.

Results

Treatment of rats with INH+RIF or INH+RIF+PZA induced hepatotoxicity as evidenced by biochemical measurements: serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) activities and the levels of total bilirubin were elevated, and the levels of albumin and total protein were decreased in drugs-treated animals. Histopathological changes were also observed in livers of animals that received drugs. Simultaneous administration of silymarin significantly decreased the biochemical and histological changes induced by the drugs.

Conclusion

The active components of silymarin had protective effects against hepatotoxic actions of drugs used in the chemotherapy of tuberculosis in animal models. Since no significant toxicity of silymarin is reported in human studies, this plant extract can be used as a dietary supplement by patients taking anti-tuberculosis medications.

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Most cited references 32

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Mechanisms of action of isoniazid.

Graham S. Timmins, Vojo Deretic (2006)

For decades after its introduction, the mechanisms of action of the front-line antituberculosis therapeutic agent isoniazid (INH) remained unclear. Recent developments have shown that peroxidative activation of isoniazid by the mycobacterial enzyme KatG generates reactive species that form adducts with NAD(+) and NADP(+) that are potent inhibitors of lipid and nucleic acid biosynthetic enzymes. A direct role for some isoniazid-derived reactive species, such as nitric oxide, in inhibiting mycobacterial metabolic enzymes has also been shown. The concerted effects of these activities - inhibition of cell wall lipid synthesis, depletion of nucleic acid pools and metabolic depression - drive the exquisite potency and selectivity of this agent. To understand INH action and resistance fully, a synthesis of knowledge is required from multiple separate lines of research - including molecular genetic approaches, in vitro biochemical studies and free radical chemistry - which is the intent of this review.

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Pyrazinamide inhibits the eukaryotic-like fatty acid synthetase I (FASI) of Mycobacterium tuberculosis.

John Welch, Tom Cox, O Zimhony … (2000)

Tuberculosis treatment is shortened to six months by the indispensable addition of pyrazinamide (PZA) to the drug regimen that includes isoniazid and rifampin. PZA is a pro-drug of pyrazinoic acid (POA) (ref. 3), whose target of action has never been identified. Although PZA is active only against Mycobacterium tuberculosis, the PZA analog 5-chloro-pyrazinamide (5-Cl-PZA) displays a broader range of anti-mycobacterial activity. We have found that the eukaryotic-like fas1 gene (encoding fatty acid synthetase I, FASI) from M. avium, M. bovis BCG or M. tuberculosis confers resistance to 5-Cl-PZA when present on multi-copy vectors in M. smegmatis. 5-Cl-PZA and PZA markedly inhibited the activity of M. tuberculosis FASI, the biosynthesis of C16 to C24/C26 fatty acids from acetyl-CoA (ref. 6). Importantly, PZA inhibited FASI in M. tuberculosis in correlation with PZA susceptibility. These results indicate that FASI is a primary target of action for PZA in M. tuberculosis. Further characterization of FASI as a drug target for PZA may allow the development of new drugs to shorten the therapy against M. tuberculosis and may provide more options for treatment against M. bovis, M. avium and drug resistant M. tuberculosis.

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Flavonoid, silibinin, inhibits proliferation and promotes cell-cycle arrest of human colon cancer.

Fawn S. Hogan, Naveen Krishnegowda, Margarita Mikhailova … (2007)

Anti-oxidative extracts from the milk thistle plant (Silybum marianum) have been shown to have antiproliferative effects in several tumor types. Silibinin is the primary active component isolated from the crude seed extract, silymarin. It has been used as a dietary supplement for hepatoprotection for over 2000 years. Silibinin has been shown to be safe in multiple animal models and has had no significant adverse events in human studies. We investigated the potential for this nontoxic flavolignan to inhibit proliferation of human colon cancer. Three well-characterized cell lines, Fet, Geo, and HCT116, were studied. The MTT cell-viability assay was performed to study the effect of silibinin on proliferation. Fluorescence-activated cell sorter (FACS) analysis was used to determine the effects of silibinin on cell cycle and apoptosis. 4', 6'-diamidine-2'-phenylindole (DAPI) staining with confocal microscopy was used to morphologically confirm these results. Poly ADP-ribose polymerase (PARP) cleavage and expression levels of p21, p27, cyclins B1/D1, and CDK-2 were measured. Cyclooxygenase-2 (COX-2) levels were also measured. The experiments were performed in triplicate and reported as mean values with standard errors. Means were contrasted using analysis of variance with Dunnet's correction for multiple testing. All statistical testing was two-sided with a significance level of 5%. The MTT assay revealed a strong dose-dependent inhibitory effect. Treatment with 75 microg/mL resulted in 50% inhibition of cell-viability (IC-50) in Fet and Geo lines at 72 h. An IC50 dose of 40 ug/mL was obtained in HCT116, a poorly-differentiated cell line, at 72 h. FACS analysis demonstrated statistically significant cell-cycle arrest in all cell lines. G(2)-M phase arrests in Fet and Geo cell lines (P < 0.001) and a G1 arrest in HCT116 (P = 0.005) were noted. Trivial increases in early apoptotic rates (2% to 3%) for Geo and HCT116 were noted on FACS analysis via annexin V-propidium iodide technique (P < 0.05), but no evidence for apoptosis was seen on Western blot for PARP cleavage or DAPI. Cyclin B1/D1 and CDK-2 levels were inhibited. Increased expression of cell cycle inhibitors, p21 or p27, was noted, and there was no effect on COX-2 expression. Silibinin significantly inhibits proliferation through cell-cycle arrest via inhibition of cyclin-CDK promoter activity. Despite its antioxidant profile, there is no effect on COX-2 expression. Apoptosis does not appear to be greatly increased in human colon cancer cell lines Fet, Geo, and HCT116. Rather, inhibition of cell cycle regulatory proteins plays a fundamental role in silibinin's mechanism of action, and this may serve as a basis for combined use with conventional chemotherapeutics.

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Author and article information

Journal

Journal ID (nlm-ta): Nutr Metab (Lond)

Title: Nutrition & Metabolism

Publisher: BioMed Central

ISSN (Electronic): 1743-7075

Publication date Collection: 2008

Publication date (Electronic): 5 July 2008

Volume: 5

Page: 18

Affiliations

[1 ]Department of Pharmacology, Marmara University, Faculty of Pharmacy, Haydarpasa, Istanbul, Turkey

[2 ]Department of Biochemistry, Marmara University, Faculty of Pharmacy, Haydarpasa, Istanbul, Turkey

Article

Publisher ID: 1743-7075-5-18

DOI: 10.1186/1743-7075-5-18

PMC ID: 2491620

PubMed ID: 18601745

SO-VID: bb1f65e9-9e27-4ab7-a072-c39ecf22f8c2

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Silymarin protects liver against toxic effects of anti-tuberculosis drugs in experimental animals

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Abstract

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Karger: Nutrition and Dietetics

Most cited references 32

Mechanisms of action of isoniazid.

Pyrazinamide inhibits the eukaryotic-like fatty acid synthetase I (FASI) of Mycobacterium tuberculosis.

Flavonoid, silibinin, inhibits proliferation and promotes cell-cycle arrest of human colon cancer.

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