Silymarin prevents benzo(a)pyrene-induced toxicity in Wistar rats by modulating xenobiotic-metabolizing enzymes

Kiruthiga, P. V.; Karthikeyan, K.; Archunan, ‪Govindaraju; Pandian, Shunmugiah Karutha; Devi, Kasi Pandima

doi:10.1177/0748233713475524

Cited by 20 publications

(22 citation statements)

References 84 publications

(86 reference statements)

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“…Silymarin, a natural compound derived from milk thistle (Silybum marianum) is widely used in health supplements, medicines, and medical supplies related to liver disease and cancer, and has no reported side-effects [50][51][52]. Previous studies on silymarin focused on its role as an anti-oxidant and its anti-inflammatory properties against B[a]P-induced ROS formation via modulating detoxifying enzymes in vivo [28]. However, B[a]P-induced genotoxicity is mainly caused by damage from BPDE-DNA adducts as well as ROS-based DNA damage.…”

Section: Discussionmentioning

confidence: 99%

“…Silymarin, a natural flavonoid, is a constituent of milk thistle (Silybum marianum). It is a metabolic regulator known to have anti-oxidant, anti-inflammatory, anti-cancer, anti-mutagenic, anti-bacterial, and anti-virus effects [27][28][29][30]. Furthermore, silymarin has multiple pharmacological activities and its components include silibinin, silydianine, and silychristin [27].…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, silymarin has multiple pharmacological activities and its components include silibinin, silydianine, and silychristin [27]. Recent studies showed that silymarin can reduce B[a]P-induced toxicity by reducing ROS formation in a rat model and can attenuate colorectal, liver, and lung cancer [28,[31][32][33]. Another report showed that silymarin also exerts anti-oxidant effects by up-regulating NQO1 and heme oxygenase 1 genes through Nrf2 modulation [33].…”

Section: Introductionmentioning

confidence: 99%

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Modulatory Effects of Silymarin on Benzo[a]pyrene-Induced Hepatotoxicity

Jee

Kim

Sung

2020

IJMS

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Benzo[a]pyrene (B[a]P), a polycyclic aromatic hydrocarbon, is a group 1 carcinogen that introduces mutagenic DNA adducts into the genome. In this study, we investigated the molecular mechanisms underlying the involvement of silymarin in the reduction of DNA adduct formation by B[a]P-7,8-dihydrodiol-9,10-epoxide (BPDE), induced by B[a]P. B[a]P exhibited toxicity in HepG2 cells, whereas co-treatment of the cells with B[a]P and silymarin reduced the formation of BPDE-DNA adducts, thereby increasing cell viability. Determination of the level of major B[a]P metabolites in the treated cells showed that BPDE levels were reduced by silymarin. Nuclear factor erythroid 2-related factor 2 (Nrf2) and pregnane X receptor (PXR) were found to be involved in the activation of detoxifying genes against B[a]P-mediated toxicity. Silymarin did not increase the expression of these major transcription factors, but greatly facilitated their nuclear translocation. In this manner, treatment of HepG2 cells with silymarin modulated detoxification enzymes through NRF2 and PXR to eliminate B[a]P metabolites. Knockdown of Nrf2 abolished the preventive effect of silymarin on BPDE-DNA adduct formation, indicating that activation of the Nrf2 pathway plays a key role in preventing B[a]P-induced genotoxicity. Our results suggest that silymarin has anti-genotoxic effects, as it prevents BPDE-DNA adduct formation by modulating the Nrf2 and PXR signaling pathways.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Modulatory Effects of Silymarin on Benzo[a]pyrene-Induced Hepatotoxicity

Jee

Kim

Sung

2020

IJMS

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“…The primary function of phase I metabolism is the ease of drug absorption and its effect on compound preparation for phase II metabolism. Phase II metabolism is detrimental to xenobiotics and drug detoxification in obtaining water-soluble products (Kiruthiga et al, 2015). In vivo studies, cyt.b 5 and cyt.b 5 R increased levels of all measured components.…”

Section: Resultsmentioning

confidence: 99%

The impacts of Elaeagnus umbellata Thunb. leaf and fruit aqueous extracts on mice hepatic, extrahepatic antioxidant and drug metabolizing enzymes related structures

Özen

Yıldırım

Toka

2018

Braz. J. Pharm. Sci.

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In this work, the potential chemopreventive activities of Elaeagnus umbellata fruit aqueous (EUFA) and leaf aqueous (EULA) extracts focusing on the modulatory influence of xenobiotic metabolizing enzymes (XMEs), antioxidant enzymes, glucose-6-phosphate dehydrogenase (G6PD), 6-phosphogluconate dehydrogenase (6PGD), lactate dehydrogenase (LDH) activity, lipid peroxidation (LP), sulfhydryl groups were investigated in the hepatic and extrahepatic organs of Swiss albino mice (50 and 100 mg/kg body wt given orally for 14 days) and compared with BHA (0.75 % in diet). The modulatory and chemopreventive properties of two different doses EUFA and EULA were observed for cytochrome P450, cytochrome b 5 , sulfhydryl groups, NADPH-cytochrome P450 reductase, NADH-cytochrome b 5 reductase, 7-ethoxyresorufin-deethylase and N,N-dimethylaniline N-oxidase activities in the liver and compared with BHA as a standard. The activities of glutathione S-transferase (GST) and DT-diaphorase (DTD) showed a significant increase in the kidney, forestomach, heart and brain at both doses of EUFA and EULA. The results of EULA-treated groups were found a notable increase in LDH, G6PD, 6PGD, GST and DTD activities. Superoxide dismutase level in liver, kidney and heart exhibited a significant increase at both doses of EULA. Glutathione reductase activity was a remarkable level at high dose of EUFA in liver, kidney and EULA in kidney. Both doses of EUFA were effective in inducing glutathione peroxidase activitiy in heart. The levels of LP at low and high doses of EULA-treated and EUFA-treated were effective in liver and kidney, respectively. The present results demonstrate that significant effects in the level of XMEs and antioxidant enzymes of EUFA and EULA are remarkable for modulating roles and natural chemoprevention properties and therefore is considered for a valuable natural source.

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“…It was concluded that the presence of CYP1A1 activated the BaP and subsequently resulted in the initiation of the said tumours. The flavonoid, silymarin was shown to block the activation of BaP in Wistar rats via the inhibition of CYP1A1 and so it is deemed to possess chemopreventive properties (Kiruthiga et al, 2013).…”

Section: Phytochemicalsmentioning

confidence: 99%

Role of the modulation of CYP1A1 expression and activity in chemoprevention

Badal

Delgoda

2014

J of Applied Toxicology

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As one of the main extra-hepatic cytochrome P450 (CYP) enzymes, CYP1A1 has been comprehensively investigated for its ability to metabolize both exogenous and endogenous compounds into their carcinogenic derivatives. These derivatives are linked to cancer initiation and progression. The compound benzo-a-pyrene (BaP), a copious and noxious compound present in coal tar, automobile exhaust fumes, cigarette smoke and charbroiled food, is metabolised by CYP1A1 and has been studied in great detail. Other compounds reliant on the same enzyme for their activation include 7,12 dimethylbenz(a)anthracene (DMBA) and heterocyclic amine, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). This review takes an in-depth look at a number of phytochemicals, plant extracts and a few synthetic compounds that have been researched and deemed potential chemopreventives via their interaction with the activity and expression of CYP1A1. It will also review a useful active site model of CYP1A1. Based on inhibitors of CYP1A1 that have demonstrated in vivo use as chemopreventors, CYP1A1 is a useful initial target for screening compounds with such potential, with the use of rapid in vitro and/or in silico assessments. Chemoprevention is a means by which healthy tissues are protected via the prevention, inhibition or reversal of carcinogenesis. This review focuses on one important pathway of carcinogenesis and identifies the important role that CYP1A1 plays in that pathway. It is hoped that highlighting the importance of such a key target, will help revive further research into and application of inhibitors of CYP1A1 towards generating improved chemopreventors.

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Silymarin prevents benzo(a)pyrene-induced toxicity in Wistar rats by modulating xenobiotic-metabolizing enzymes

Cited by 20 publications

References 84 publications

Modulatory Effects of Silymarin on Benzo[a]pyrene-Induced Hepatotoxicity

Modulatory Effects of Silymarin on Benzo[a]pyrene-Induced Hepatotoxicity

The impacts of Elaeagnus umbellata Thunb. leaf and fruit aqueous extracts on mice hepatic, extrahepatic antioxidant and drug metabolizing enzymes related structures

Role of the modulation of CYP1A1 expression and activity in chemoprevention

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