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

2020 ◽  
Vol 21 (7) ◽  
pp. 2369 ◽  
Author(s):  
Seung-Cheol Jee ◽  
Min Kim ◽  
Jung-Suk Sung
Keyword(s):  
Dna Adducts ◽  
Hepg2 Cells ◽  
Molecular Mechanisms ◽  
Nuclear Translocation ◽  
Pregnane X Receptor ◽  
Adduct Formation ◽  
Dna Adduct ◽  
Detoxification Enzymes ◽  
Related Factor ◽  
Polycyclic Aromatic

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.

Molecular Dosimetry of DNA Damage Induced by Polycyclic Aromatic Hydrocarbons; Relevance for Exposure Monitoring and Risk Assessment

1994 ◽  
Vol 13 (12) ◽  
pp. 880-887 ◽  
Author(s):  
R.A. Baan ◽  
M.-J.S.T. Steenwinkel ◽  
P.T.M. van den Berg ◽  
R. Roggeband ◽  
J.H.M. van Delft
Keyword(s):  
Dna Damage ◽  
Dna Adducts ◽  
Aromatic Hydrocarbons ◽  
Blood Cells ◽  
Adduct Formation ◽  
Dna Adduct ◽  
Immunochemical Analysis ◽  
Basal Cells ◽  
Polycyclic Aromatic

Polycyclic aromatic hydrocarbons (PAH) form a large group of organic chemicals that are widely distributed in our environment as pollutants of air, water and soil. Several PAH are carcinogenic in rodents, while exposure to these compounds has been associated with various types of human cancer. Upon entering the body, PAH may be converted into reactive electrophilic species, which can give rise to the formation of DNA adducts. DNA adduct formation is considered to be the initial event in chemical carcinogenesis. In this paper, two methods are illustrated that are widely used to determine PAH-DNA adduct formation, namely 32P-postlabelling, and immunochemical analysis with specific antibodies. The applications of the 32P-postlabelling assay comprise the following: - A study of interspecies differences in PAH bioactivation in vitro, with microsomal preparations isolated from liver tissue of various rodent species and of human origin; the results indicate that there are considerable qualitative differences between the adduct patterns obtained, which is relevant with respect to extrapolation from animal to man. - The analysis of DNA adduct formation in fish retrieved from marine environments polluted to various extents with PAH; results of these studies show a correlation between liver-DNA adduct levels in these fish and the degree of PAH contamination in the aquatic environment. - Biomonitoring of PAH exposure through analysis of adducts in blood cells obtained from heavy and light smokers; the data show a fair correlation between PAH-DNA adduct levels in white blood cells and cotinine content in blood plasma, the latter being used as a marker for exposure to cigarette smoke. The activity of the detoxifying enzyme glutathione S-transferase M (GSTM1) was also determined in these individuals. Immunochemical analysis with a benzo(a)pyrene(BP)-DNA-specific antiserum was used to investigate BP-adduct induction in situ, in different epithelial cell types—basal/non—basal cells—of hamster trachea exposed to BP in vitro, Histochemical staining of cell-specific cytokeratins was combined with adduct-specific immunostaining. The latter was quantified by immunofluorescence microscopy. The results show that removal of DNA adducts from the basal cells is more rapid during the first 24 h following exposure than from the non-basal cells. The sensitive methods for molecular dosimetry of DNA damage, as illustrated in this paper, appear suitable for determining exposure of animals and humans to PAH. Further animal experiments and in vitro model studies will provide useful additional information that will help evaluate the relevance of biomonitoring data with respect to the health risk that may be associated with the exposure.

scholarly journals Sulfuric Odor Precursor S-Allyl-l-Cysteine Sulfoxide in Garlic Induces Detoxifying Enzymes and Prevents Hepatic Injury

Antioxidants ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 385 ◽  
Author(s):  
Yusuke Yamaguchi ◽  
Ryosuke Honma ◽  
Tomoaki Yazaki ◽  
Takeshi Shibuya ◽  
Tomoya Sakaguchi ◽  
...  
Keyword(s):  
Small Intestine ◽  
Hepg2 Cells ◽  
Hepatic Injury ◽  
Nuclear Translocation ◽  
Water Soluble ◽  
Diallyl Disulfide ◽  
Related Factor ◽  
Detoxifying Enzymes ◽  
Odor Compounds ◽  
Cysteine Sulfoxide

S-Allyl-l-cysteine sulfoxide (ACSO) is a precursor of garlic-odor compounds like diallyl disulfide (DADS) and diallyl trisulfide (DATS) known as bioactive components. ACSO has suitable properties as a food material because it is water-soluble, odorless, tasteless and rich in bulbs of fresh garlic. The present study was conducted to examine the preventive effect of ACSO on hepatic injury induced by CCl4 in rats. ACSO, its analogs and garlic-odor compounds were each orally administered via gavage for five consecutive days before inducing hepatic injury. Then, biomarkers for hepatic injury and antioxidative state were measured. Furthermore, we evaluated the absorption and metabolism of ACSO in the small intestine of rats and NF-E2-related factor 2 (Nrf2) nuclear translocation by ACSO using HepG2 cells. As a result, ACSO, DADS and DATS significantly suppressed the increases in biomarkers for hepatic injury such as the activities of aspartate transaminase (AST), alanine transaminase (ALT) and lactate dehydrogenase (LDH), and decreases in antioxidative potency such as glutathione (GSH) level and the activities of glutathione S-transferase (GST) and glutathione peroxidase (GPx). We also found ACSO was absorbed into the portal vein from the small intestine but partially metabolized to DADS probably in the small intestine. In in vitro study, ACSO induced Nrf2 nuclear translocation in HepG2 cells, which is recognized as an initial trigger to induce antioxidative and detoxifying enzymes. Taken together, orally administered ACSO probably reached the liver and induced antioxidative and detoxifying enzymes by Nrf2 nuclear translocation, resulting in prevention of hepatic injury. DADS produced by the metabolism of ACSO in the small intestine might also have contributed to the prevention of hepatic injury. These results suggest potential use of ACSO in functional foods that prevent hepatic injury and other diseases caused by reactive oxygen species (ROS).

Exposure-route-dependent DNA adduct formation by polycyclic aromatic hydrocarbons

2000 ◽  
Vol 21 (1) ◽  
pp. 87-92 ◽  
Author(s):  
Roger W.L. Godschalk ◽  
Edwin J.C. Moonen ◽  
Pauline A.E.L. Schilderman ◽  
Wendy M.R. Broekmans ◽  
Jos C.S. Kleinjans ◽  
...  
Keyword(s):  
Polycyclic Aromatic Hydrocarbons ◽  
Aromatic Hydrocarbons ◽  
Adduct Formation ◽  
Dna Adduct ◽  
Exposure Route ◽  
Polycyclic Aromatic

scholarly journals Molecular Mechanisms Underlying Hepatocellular Carcinoma Induction by Aberrant NRF2 Activation-Mediated Transcription Networks: Interaction of NRF2-KEAP1 Controls the Fate of Hepatocarcinogenesis

2020 ◽  
Vol 21 (15) ◽  
pp. 5378 ◽  
Author(s):  
Effi Haque ◽  
M. Rezaul Karim ◽  
Aamir Salam Teeli ◽  
Magdalena Śmiech ◽  
Paweł Leszczynski ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Leucine Zipper ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Precancerous Lesions ◽  
Redox Homeostasis ◽  
Detoxification Enzymes ◽  
Related Factor ◽  
Basic Leucine Zipper ◽  
Nrf2 Activation

NF-E2-related factor 2 (NRF2) is a basic leucine zipper transcription factor, a master regulator of redox homeostasis regulating a variety of genes for antioxidant and detoxification enzymes. NRF2 was, therefore, initially thought to protect the liver from oxidative stress. Recent studies, however, have revealed that mutations in NRF2 cause aberrant accumulation of NRF2 in the nucleus and exert the upregulation of NRF2 target genes. Moreover, among all molecular changes in hepatocellular carcinoma (HCC), NRF2 activation has been revealed as a more prominent pathway contributing to the progression of precancerous lesions to malignancy. Nevertheless, how its activation leads to poor prognosis in HCC patients remains unclear. In this review, we provide an overview of how aberrant activation of NRF2 triggers HCC development. We also summarize the emerging roles of other NRF family members in liver cancer development.

scholarly journals Bile acid detoxifying enzymes limit susceptibility to liver fibrosis in female SHRSP5/Dmcr rats fed with a high-fat-cholesterol diet

2017 ◽  
Author(s):  
Husna Yetti ◽  
Hisao Naito ◽  
Yuan Yuan ◽  
Xiaofang Jia ◽  
Yumi Hayashi ◽  
...  
Keyword(s):  
Bile Acid ◽  
Nuclear Receptors ◽  
Molecular Mechanisms ◽  
Pregnane X Receptor ◽  
Mature Female ◽  
Farnesoid X Receptor ◽  
Detoxification Enzymes ◽  
Cytochrome P450 Enzymes ◽  
High Fat ◽  
Expression Levels

During middle age, women are less susceptible to nonalcoholic steatohepatitis (NASH) than men. Thus, we investigated the underlying molecular mechanisms behind these sexual differences using an established rat model of NASH. Mature female and male stroke-prone spontaneously hypertensive 5/Dmcr rats were fed control or high-fat-cholesterol (HFC) diets for 2, 8, and 14 weeks. Although HFC-induced hepatic fibrosis was markedly less severe in females than in males, only minor gender differences were observed in expression levels of cytochrome P450 enzymes (CYP)7A1, CYP8B1 CYP27A1, and CYP7B1, and multidrug resistance-associated protein 3, and bile salt export pump, which are involved in fibrosis-related bile acid (BA) kinetics. However, the BA detoxification-related enzymes UDP-glucuronosyltransferase (UGT) and sulfotransferase (SULT) 2A1, and the nuclear receptors constitutive androstene receptor (CAR) and pregnane X receptor (PXR), were strongly suppressed in HFC fed males, and were only slightly changed in HFC-diet fed females. Expression levels of the farnesoid X receptor and its small heterodimer partner were similarly regulated in a gender-dependent fashion following HFC feeding. Hence, the pronounced female resistance to HFC-induced liver damage likely reflects sustained expression of the nuclear receptors CAR and PXR and the BA detoxification enzymes UGT and SULT.

scholarly journals Curcumin Suppresses the Lipid Accumulation and Oxidative Stress Induced by Benzo[a]pyrene Toxicity in HepG2 Cells

Antioxidants ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1314
Author(s):  
Seung-Cheol Lee ◽  
Seung-Cheol Jee ◽  
Min Kim ◽  
Soee Kim ◽  
Min Kyoung Shin ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cytochrome P450 ◽  
Cell Viability ◽  
Lipid Accumulation ◽  
Hepg2 Cells ◽  
Nuclear Translocation ◽  
The Body ◽  
Ros Generation ◽  
Related Factor ◽  
And Oxidative Stress

Benzo[a]pyrene (B[a]P) is a potentially hepatotoxic group-1 carcinogen taken up by the body through ingestion of daily foods. B[a]P is widely known to cause DNA and protein damages, which are closely related to cell transformation. Accordingly, studies on natural bioactive compounds that attenuate such chemical-induced toxicities have significant impacts on public health. This study aimed to uncover the mechanism of curcumin, the major curcuminoid in turmeric (Curcuma longa), in modulating the lipid accumulation and oxidative stress mediated by B[a]P cytotoxicity in HepG2 cells. Curcumin treatment reduced the B[a]P-induced lipid accumulation and reactive oxygen spicies (ROS) upregulation and recovered the cell viability. Cytochrome P450 family 1 subfamily A polypeptide 1 (CYP1A1) and Cytochrome P450 subfamily B polypeptide 1 (CYP1B1) downregulation resulting from decreased aryl hydrocarbon receptor (AhR) translocation into nuclei attenuated the effects of B[a]P-induced lipid accumulation and repressed cell viability, respectively. Moreover, the curcumin-induced reduction in ROS generation decreased the nuclear translocation of Nuclear factor erythroid-2-related factor 2 (Nrf2) and the expression of phase-II detoxifying enzymes. These results indicate that curcumin suppresses B[a]P-induced lipid accumulation and ROS generation which can potentially induce nonalcoholic fatty liver disease (NAFLD) and can shed a light on the detoxifying effect of curcumin.

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