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

Beckmann-Knopp, S; Rietbrock, Stephan; Weyhenmeyer, Roland; Böcker, R; Beckurts, K. T. E.; Lang, Wenhua; Hunz, M; Fuhr, Uwe

doi:10.1111/j.0901-9928.2000.860602.x

Cited by 129 publications

(106 citation statements)

References 31 publications

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“…MTX inhibits the synthesis of DNA, RNA, thymidylate and proteins. As a result of this activity, MTX is commonly used in cancer treatment, in addition to the treatment of non-neoplastic diseases, including rheumatoid arthritis and psoriasis (1). Previous studies have demonstrated that liver, kidney, brain and lung toxicities are potential side effects of MTX use (2).…”

Section: Introductionmentioning

confidence: 99%

Silibinin attenuates methotrexate-induced pulmonary injury by targeting oxidative stress

Kalemci

Topal

Celi̇k

et al. 2015

Experimental and Therapeutic Medicine

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Abstract. The aim of the present study was to assess the protective effect of silibinin against methotrexate (MTX)-induced pulmonary toxicity. Rats were divided into four groups (MTX, MTX + silibinin, silibinin and control. MTX was injected intraperitoneally (i.p) into female Wistar rats (10 mg/kg/day for 3 days), which resulted in significant increases in the serum levels of alanine aminotransferase, aspartate aminotransferase and oxidant enzymes, including nitric oxide and myeloperoxidase. Furthermore, significant reductions were detected in the serum activity levels of the antioxidative enzymes, glutathione peroxidase and superoxide dismutase, when compared with the control group. However, administration of silibinin (100 mg/kg/day for 10 days, i.p.) was shown to ameliorate the MTX-induced pulmonary toxicity, as indicated by the normalization of the oxidative stress parameters. Furthermore, silibinin treatment was demonstrated to reduce the histopathological changes associated with MTX. In conclusion, silibinin exhibited protective effects against MTX-induced pulmonary toxicity, which may be attributed to its antioxidant activity.

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Section: Introductionmentioning

confidence: 99%

Silibinin attenuates methotrexate-induced pulmonary injury by targeting oxidative stress

Kalemci

Topal

Celi̇k

et al. 2015

Experimental and Therapeutic Medicine

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“…The active constituents of S. marianum may strengthen or stimulate the immune response by interacting with various parameters of the immune system. The reported positive effect of herbal medicine has been expressed by a number of mechanisms, e.g., inhibition of tumor necrosis factor TNF-α, interferon IFN-γ, interleukin IL-2, IL-4, and nuclear factor-kappa B (NF-ĸB) activation in rat (Wilasrusmee et al 2002, Ardestani andYazdanparast 2007), inhibition of fibrosis in rat (Jia et al 2001), inhibition of inflammation (Kaur andAgarwal 2007, Ramasamy andAgarwal 2008), immunomodulation in mice (Schümann et al 2003), inhibition of mitochondrial injury in rat (Rolo et al 2003), inhibition of P450 activity in human liver microsomes (Beckmann-Knopp et al 2000), antioxidant properties and inhibition of lipid peroxidation in rat and fish (Han et al 2007, Toklu et al 2007, Banaee et al 2011, enhancement of RNA, DNA (Sonnenbichler et al 1984), protein synthesis in liver tissue of rainbow trout (Banaee et al 2011), regulation of cell permeability (Kiruthiga et al 2007, Basiglio et al 2009), and adjustment of enzyme levels activity in plasma (Banaee et al 2011).…”

Section: Introductionmentioning

confidence: 99%

Evaluation of the Immunomodulatory Effects of Silymarin Extract (<I>Silybum Marianum</I>) on Some Immune Parameters of Rainbow Trout, <I>Oncorhynchus Mykiss</I> (Actinopterygii: Salmoniformes: Salmonidae)

Ahmadi¹,

Banaee²,

Vosoghei³

et al. 2012

Acta Icth et Piscat

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Ataeimehr B. 2012. Evaluation of the immunomodulatory effects of silymarin extract (Silybum marianum) on some immune parameters of rainbow trout, Oncorhynchus mykiss (Actinopterygii: Salmoniformes: Salmonidae). Acta Ichthyol. Piscat. 42 (2): 113-120.Background. Herbal medicines are increasingly used for their effects on the immune system. Silymarin, a mixture of flavonolignans from the seed of milk thistle (Silybum marianum), is used in treatment of liver disease, food and drug poising, and foetal diseases such as viral hepatitis, diabetes, and ischemia. Although, immunostimulant effects of the dietary silymarin were studied on different experimental animals, no information is available about the effects of silymarin on immune parameters of fish. The presently reported study was conducted to investigate the immunomodulatory effects of silymarin on some immunological and haematological parameters of rainbow trout. Materials and methods. Juvenile rainbow trout, Oncorhynchus mykiss (Walbaum, 1792), were maintained in 1000 L fiberglass tanks at 15 ± 2ºC supplied with systems of water recirculation and aeration. Silymarin extract incorporated into diets (0.0, 0.1, 0.4, and 0.8 g of per 1 kg of feed) of fish. The trout were fed silymarin-supplemented diet for 30 days. Haematological parameters, such as red blood cell count (RBC), white blood cell count (WBC), haematocrit (Hct), haemoglobin (Hb), differential leukocyte-and immunological parameters such as peroxidase, lysozyme, and complement activities, total protein, albumin and globulin levels were measured on day 7, 15, and 30 days of silymarin treatment. Results. The results indicated that oral administration of silymarin in fish, after 15 and 30 days of experimental periods, might enhance haematological and immunological parameters including lysozyme and complement activities, total protein and globulin levels, compared to the controls. Conclusion. The results suggest that oral administration of silymarin may be useful to strengthen the immune system in rainbow trout.

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“…Although the administration of silymarin is considered safe with minimal adverse events, the competitive interaction of silybin with cytochromes P450 (P450s 1 ) and the potential for drug interactions were recently reported (Beckmann-Knopp et al, 2000). The importance of phase I biotransformation, mainly facilitated by cytochromes P450, in the oxidative metabolism and eventual detoxification of drugs and xenobiotics is well recognized (Guengerich, 1991).…”

mentioning

confidence: 99%

“…Importantly, glucuronidation facilitated by UDP-glucuronosyltransferases (UGTs) is increasingly recognized as a major phase II detoxification pathway in humans (Fisher et al, 2001), and silybin may exert effects on both phase I and phase II metabolic reactions. For instance, silybin has been shown to noncompetitively inhibit denitronifedipine oxidation, mediated by P450 3A4 (K i ϭ 11 M), in human liver microsomes (Beckmann-Knopp et al, 2000). Competitive inhibition was reported for S(Ϫ)-warfarin 7-hydroxylation (P450 2C9; K i ϭ 19 M).…”

mentioning

confidence: 99%

“…Dextromethorphan (P450 2D6) was characterized as a competitive inhibitor, with high inhibition potency observed for a low binding site (K i ) and vice versa (Beckmann-Knopp et al, 2000). Negligible effects on the metabolism of erythromycin (P450 3A4), chlorzoxazone (P450 2E1), S(ϩ)-mephenytoin (P450 2C19), caffeine (P450 1A2), and coumarin (P450 2A6) were observed.…”

mentioning

confidence: 99%

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Silybin Inactivates Cytochromes P450 3a4 and 2c9 and Inhibits Major Hepatic Glucuronosyltransferases

Sridar¹,

Goosen

Kent³

et al. 2004

Drug Metab Dispos

174

154

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ABSTRACT:Silybin, a major constituent of the milk thistle, is used to treat several liver disorders. Silybin inactivated purified, recombinant cytochromes P450 (P450) 3A4 and 2C9 in a mechanism-based manner. The inactivations were time-, concentration-, and NADPHdependent. The inactivation of the 7-benzyloxy-4-(trifluoromethyl-)coumarin O-debenzylation activity (P450 3A4) was characterized by a K I of 32 M, a k inact of 0.06 min ؊1 , and a t 1/2 of 14 min.Testosterone metabolism to 6-␤-hydroxytestosterone (P450 3A4) was also inactivated with a K I of 166 M, a k inact of 0.08 min ؊1, and a t 1/2 of 9 min. The 7-ethoxy-4-(trifluoromethyl)coumarin O-deethylation activity of purified human P450 2C9 was inactivated with a K I of 5 M, a k inact of 0.14 min ؊1, and a t 1/2 of 7 min. Parallel loss of heme was observed with both P450s. Activity of both P450 enzymes was not recovered after removal of silybin either by dialysis or by spin gel filtration. In addition, silybin inhibited the glucuronidation of 7-hydroxy-4-trifluoromethylcoumarin catalyzed by recombinant hepatic UDP-glucuronosyltransferases (UGTs) 1A1, 1A6, 1A9, 2B7, and 2B15, with IC 50 values of 1.4 M, 28 M, 20 M, 92 M, and 75 M, respectively. Silybin was a potent inhibitor of UGT1A1 and was 14-and 20-fold more selective for UGT1A1 than for UGT1A9 and UGT1A6, respectively. Thus, careful administration of silybin with drugs primarily cleared by P450s 3A4 or 2C9 is advised, since drug-drug interactions cannot be excluded. The clinical significance of in vitro UGT1A1 inhibition is unknown.

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

Cited by 129 publications

References 31 publications

Silibinin attenuates methotrexate-induced pulmonary injury by targeting oxidative stress

Silibinin attenuates methotrexate-induced pulmonary injury by targeting oxidative stress

Evaluation of the Immunomodulatory Effects of Silymarin Extract (<I>Silybum Marianum</I>) on Some Immune Parameters of Rainbow Trout, <I>Oncorhynchus Mykiss</I> (Actinopterygii: Salmoniformes: Salmonidae)

Silybin Inactivates Cytochromes P450 3a4 and 2c9 and Inhibits Major Hepatic Glucuronosyltransferases

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