Hepatoprotective mechanism of silymarin: No evidence for involvement of cytochrome P450 2E1

Míguez, María Prado; Anundi, Iréne; Sainz-Pardo, L.A.; Lindros, Kai O.

doi:10.1016/0009-2797(94)90006-x

Cited by 82 publications

(56 citation statements)

References 25 publications

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“…there is no evidence of the interaction of silymarin or silibinin with cytochrome P450-2E1, thus suggesting that these antitoxic effects are due to its antioxidant and free radical scavenging properties (Miguez et al, 1994).…”

Section: Antioxidant Effectsmentioning

confidence: 97%

Milk thistle in liver diseases: past, present, future

Abenavoli

Capasso²,

Milić

et al. 2010

Phytotherapy Research

503

350

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Silybum marianum or milk thistle (MT) is the most well‐researched plant in the treatment of liver disease. The active complex of MT is a lipophilic extract from the seeds of the plant and is composed of three isomer flavonolignans (silybin, silydianin, and silychristin) collectively known as silymarin. Silybin is a component with the greatest degree of biological activity and makes up 50% to 70% of silymarin. Silymarin is found in the entire plant but it is concentrated in the fruit and seeds. Silymarin acts as an antioxidant by reducing free radical production and lipid peroxidation, has antifibrotic activity and may act as a toxin blockade agent by inhibiting binding of toxins to the hepatocyte cell membrane receptors. In animals, silymarin reduces liver injury caused by acetaminophen, carbon tetrachloride, radiation, iron overload, phenylhydrazine, alcohol, cold ischaemia and Amanita phalloides. Silymarin has been used to treat alcoholic liver disease, acute and chronic viral hepatitis and toxin‐induced liver diseases. Copyright © 2010 John Wiley & Sons, Ltd.

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Section: Antioxidant Effectsmentioning

confidence: 97%

Milk thistle in liver diseases: past, present, future

Abenavoli

Capasso²,

Milić

et al. 2010

Phytotherapy Research

503

350

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“…Silibinin at concentrations of 50 mM or 500 mM had no protective effects in isolated human hepatocytes treated with tetrachlormethan or acet-aminophen which are activated by CYP2E1. The conclusion of the authors was that silibinin does not inhibit this enzyme (Miguez et al 1994).…”

mentioning

confidence: 97%

“…In these investigations, such flavonoids reduced hepatocyte damage caused by administration of various chemicals including, among others, allyl alcohol (Miguez et al 1994), carbon tetrachloride (Mourelle et al 1989), halo-thane (Siegers et al 1983), acetaminophen (Muriel et al 1992) and phenylhydrazine (Valenzuela et al 1985). Several mechanisms of action were discussed: (1) stimulation of protein synthesis in the hepatocytes (Machicao & Sonnenbichler 1977), (2) radical scavenging and antioxidant properties (Ubeda et al 1995), (3) prevention of penetration of toxins into the cell (Münter et al 1986), and (4) inhibition of 5-lipoxygenase with reduced formation of leucotriens (Dehmlow et al 1996).…”

mentioning

confidence: 98%

“…In the present investigation the inhibitory effect of silibinin on the activity of the seven most important human cytochrome P-450 enzymes in drug metabolism, including CYP2D6, 3A4, 1A2, 2E1, 2C19, 2C9, and 2A6, was studied in human liver microsomal incubations using selective substrates (Fuhr et al 1996a;Bertz & Grannemann 1997). Although Miguez et al (1994) had already published data related to silibinin effects on human CYP2E1, we also included CYP2E1 in our studies for comparison. In the case of CYP3A4, two model substrates were used, i.e.…”

mentioning

confidence: 99%

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Inhibitory Effects of Silibinin on Cytochrome P‐450 Enzymes in Human Liver Microsomes

Beckmann-Knopp¹,

Rietbrock²,

Weyhenmeyer³

et al. 2000

Pharmacology & Toxicology

130

101

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Silibinin, the main constituent of silymarin, a flavonoid drug from silybum marianum used in liver disease, was tested for inhibition of human cytochrome P-450 enzymes. Metabolic activities were determined in liver microsomes from two donors using selective substrates. With each substrate, incubations were carried out with and without silibinin (concentrations 3.7-300 mM) at 37ae in 0.1 M KH 2 PO 4 buffer containing up to 3% DMSO. Metabolite concentrations were determined by HPLC or direct spectroscopy. First, silibinin IC 50 values were determined for each substrate at respective K M concentrations. Silibinin had little effect (IC 50 Ͼ200 mM) on the metabolism of erythromycin (CYP3A4), chlorzoxazone (CYP2E1), S(π)-mephenytoin (CYP2C19), caffeine (CYP1A2) or coumarin (CYP2A6). A moderate effect was observed for high affinity dextromethorphan metabolism (CYP2D6) in one of the microsomes samples tested only (IC 50 Ω173 mM). Clear inhibition was found for denitronifedipine oxidation (CYP3A4; IC 50 Ω29 mM and 46 mM) and S(ª)-warfarin 7-hydroxylation (CYP2C9; IC 50 Ω43 mM and 45 mM). When additional substrate concentrations were tested to assess enzyme kinetics, silibinin was a potent competitive inhibitor of dextromethorphan metabolism at the low affinity site, which is not CYP2D6 (K i,c Ω2.3 mM and 2.4 mM). Inhibition was competitive for S(ª)-warfarin 7-hydroxylation (K i,c Ω18 mM and 19 mM) and mainly non-competitive for denitronifedipine oxidation (K i,n Ω9 mM and 12 mM). With therapeutic silibinin peak plasma concentrations of 0.6 mM and biliary concentrations up to 200 mM, metabolic interactions with xenobiotics metabolised by CYP3A4 or CYP2C9 cannot be excluded.

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“…It was first thought to be a single compound with the structure of 7-chromanol-3-methyltaxifolin; recently it was found to be a mixture of several compounds namely silybin, isosilybin, silydianin and silychristin [22,23]. Silymarin's hepatoprotective effects are accomplished via several mechanisms including antioxidation, free radical scavenging properties and stabilisation of cell membrane [20,21,24,27], inhibition of lipid peroxidation [28,29], protection of glutathione depletion [30]. Recently, studies have shown silymarin exhibits several anti-inflammatory effects [31,32].…”

Section: Resultsmentioning

confidence: 99%

Total Polyphenolic Content and Antioxidant Activity of Silybum Marianum Cultures Grown on Different Growth Regulators

Mekky

Sohafy

El-khair

et al. 2017

Int J Pharm Pharm Sci

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Objective: The present study was designed to study the effect of supplementing Silybum marianum cultures with different combinations and concentrations of growth regulators on the total phenolic content and the antioxidant activity of the produced cultures. Methods:The total polyphenolic content of 23 extracts of calli was calculated as µg of gallic acid/mg of dry weight extract (DWE) using FolinCiocalteu reagent. The antioxidant activity was calculated as trolox equivalent antioxidant capacity using 1,1-Diphenyl-2-picryl-hydrazyl (DPPH) assay for extracts containing more than 10 µg gallic acid/mg DWE.Results: Most of the combinations showed an increase in the total polyphenolic concentration compared to the wild plant. However, cultures grown on media supplemented with combinations of benzyl aminopurine (BAP) and gebberellic acid (Gb), adenine (Ad) and kinetin (Kin), BAP and indole acetic acid (IAA) possessed the highest total polyphenolic contents 20.5, 13.09 and 12.15 µg gallic acid/mg DWE, respectively. However, only (BAP+Gb), (BAP+1-Naphthaleneacetic acid (NAA), IAA, kin and (BAP+Ad) showed a significant increase in the antioxidant activity calculated as trolox equivalent with 2.65, 1.56, 1.56, 1.35 and 1.22 folds increase over the wild plant, respectively. Conclusion:The results obtained clearly indicated that changing the growth regulator system of Silybum marianum cultures serves as an easy and reliable method for increasing the total phenolic content and the antioxidant activity of cultures.

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Hepatoprotective mechanism of silymarin: No evidence for involvement of cytochrome P450 2E1

Cited by 82 publications

References 25 publications

Milk thistle in liver diseases: past, present, future

Milk thistle in liver diseases: past, present, future

Inhibitory Effects of Silibinin on Cytochrome P‐450 Enzymes in Human Liver Microsomes

Total Polyphenolic Content and Antioxidant Activity of Silybum Marianum Cultures Grown on Different Growth Regulators

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