Silymarin attenuates benzo(a)pyrene induced toxicity by mitigating ROS production, DNA damage and calcium mediated apoptosis in peripheral blood mononuclear cells (PBMC)

Vijayaraman, Kiruthiga Perumal; Muruganantham, Shanmuganathan; Subramanian, Manickavalli; Shunmugiah, Karutha Pandian; Kasi, Pandima Devi

doi:10.1016/j.ecoenv.2012.08.031

Cited by 28 publications

(13 citation statements)

References 32 publications

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“…Other than its mutagenic and carcinogenic properties, B[a]P has been well documented to cause ROS-realted toxicity 22 , 23 . An increased ROS level is known to cause wide-range of damages, including cell death and to protect themselves against these damages, the cells alters the expression of genes encoding antioxidants and other metabolic enzymes 24 .…”

Section: Discussionmentioning

confidence: 99%

Benzo[a]pyrene-induced metabolic shift from glycolysis to pentose phosphate pathway in the human bladder cancer cell line RT4

Verma

Pink

Boland

et al. 2017

Sci Rep

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Benzo[a]pyrene (B[a]P), a well-known polyaromatic hydrocarbon, is known for its lung carcinogenicity, however, its role in bladder cancer development is still discussed. Comparative two-dimensional blue native SDS-PAGE analysis of protein complexes isolated from subcellular fractions of 0.5 µM B[a]P-exposed cells indicated a differential regulation of proteins involved in carbohydrate, fatty acid, and nucleotide metabolism, suggesting a possible metabolic flux redistribution. It appeared that B[a]P exposure led to a repression of enzymes (fructose-bisphosphate aldolase A, glucose-6-phosphate isomerase, lactate dehydrogenase) involved in glycolysis, and an up-regulation of proteins (glucose-6-phosphate 1-dehydrogenase, 6-phosphogluconolactonase) catalyzing the pentose phosphate pathway and one carbon metabolism (10-formyltetrahydrofolate dehydrogenase, bifunctional purine biosynthesis protein). Untargeted metabolomics further supported the proteomic data, a lower concentration of glycolytic metabolite was observed as compared to glutamine, xylulose and fatty acids. The analysis of the glutathione and NADPH/NADP+ content of the cells revealed a significant increase of these cofactors. Concomitantly, we did not observe any detectable increase in the production of ROS. With the present work, we shed light on an early phase of the metabolic stress response in which the urothelial cells are capable of counteracting oxidative stress by redirecting the metabolic flux from glycolysis to pentose phosphate pathway.

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Section: Discussionmentioning

confidence: 99%

Benzo[a]pyrene-induced metabolic shift from glycolysis to pentose phosphate pathway in the human bladder cancer cell line RT4

Verma

Pink

Boland

et al. 2017

Sci Rep

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“…In experiments with benzo(a)pyrene (B(a)P), an environmental contaminant causing oxidative stress, the protective effect of SM/silibinin (400–500 μM) was shown. It was associated with decreasing DNA damage and apoptosis [ 112 ], preventing protein thiol oxidation and AO enzyme (SOD, GSH-Px, CAT, GR, GST) inhibition in the hemolysate [ 113 ], restoring redox status, modulating glutathione metabolizing enzymes, decreasing formation of protein oxidation products and changing the level of antioxidant enzymes (5 mM; [ 114 ]). SM (50–250 mg/kg/BW) showed substantial protective effects against B(a)P-induced damages by inhibiting phase I detoxification enzyme CYP1A1 and modulating phase II conjugating enzymes (glutathione- S -transferase, epoxide hydroxylases, uridine diphosphate glucuronosyltransferases, NAD(P)H: quinone oxidoreductase 1, sulfotransferases) in rat liver [ 115 ].…”

Section: Antioxidant Properties Of Silymarin (Sm)mentioning

confidence: 99%

Silymarin as a Natural Antioxidant: An Overview of the Current Evidence and Perspectives

2015

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Silymarin (SM), an extract from the Silybum marianum (milk thistle) plant containing various flavonolignans (with silybin being the major one), has received a tremendous amount of attention over the last decade as a herbal remedy for liver treatment. In many cases, the antioxidant properties of SM are considered to be responsible for its protective actions. Possible antioxidant mechanisms of SM are evaluated in this review. (1) Direct scavenging free radicals and chelating free Fe and Cu are mainly effective in the gut. (2) Preventing free radical formation by inhibiting specific ROS-producing enzymes, or improving an integrity of mitochondria in stress conditions, are of great importance. (3) Maintaining an optimal redox balance in the cell by activating a range of antioxidant enzymes and non-enzymatic antioxidants, mainly via Nrf2 activation is probably the main driving force of antioxidant (AO) action of SM. (4) Decreasing inflammatory responses by inhibiting NF-κB pathways is an emerging mechanism of SM protective effects in liver toxicity and various liver diseases. (5) Activating vitagenes, responsible for synthesis of protective molecules, including heat shock proteins (HSPs), thioredoxin and sirtuins and providing additional protection in stress conditions deserves more attention. (6) Affecting the microenvironment of the gut, including SM-bacteria interactions, awaits future investigations. (7) In animal nutrition and disease prevention strategy, SM alone, or in combination with other hepatho-active compounds (carnitine, betaine, vitamin B12, etc.), might have similar hepatoprotective effects as described in human nutrition.

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“…In the body, defense systems against xenobiotics such as BPDE include the activation of detoxifying phase II and III enzymes to prevent further cellular damage; specifically, glutathione S-transferases (GSTs) [14], nicotinamide adenine dinucleotide phosphate (NAD(P)H): quinone oxidoreductase 1 (NQO1), sulfotransferases (SULTs), and multidrug resistance-associated proteins (ABCCs) [15][16][17]. Previous studies showed that the genotoxicity of B[a]P was reduced by phase II enzymes conjugated with B[a]P metabolites and that B[a]P was excreted by ABCCs before BPDE-DNA adducts could form [18][19][20].…”

Section: Introductionmentioning

confidence: 99%

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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Silymarin attenuates benzo(a)pyrene induced toxicity by mitigating ROS production, DNA damage and calcium mediated apoptosis in peripheral blood mononuclear cells (PBMC)

Cited by 28 publications

References 32 publications

Benzo[a]pyrene-induced metabolic shift from glycolysis to pentose phosphate pathway in the human bladder cancer cell line RT4

Benzo[a]pyrene-induced metabolic shift from glycolysis to pentose phosphate pathway in the human bladder cancer cell line RT4

Silymarin as a Natural Antioxidant: An Overview of the Current Evidence and Perspectives

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

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