Genistein Affects Expression of Cytochrome P450 (CYP450) Genes in Hepatocellular Carcinoma (HEPG2/C3A) Cell Line

Lepri, Sandra Regina; Sartori, Daniele; Semprebon, Simone Cristine; Baranoski, Adrivânio; Coatti, Giuliana Castello; Mantovani, Mário

doi:10.2174/1872312812666180709150440

Cited by 17 publications

(12 citation statements)

References 55 publications

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“…In our assessment of genistein-induced hepatotoxicity, we observed a decreased cell viability at this concentration. Other groups, however, did not observe any impairment in cell viability after treatment with up to 100 µM in the human hepatoma cell line HepG2 [ 53 , 54 ], possibly due to a stronger resilience of the immortalized cell line. Another recent publication reported repeated viability assessments of genistein-treated HepG2 cells [ 55 ].…”

Section: Discussionmentioning

confidence: 99%

Influence of Genistein on Hepatic Lipid Metabolism in an In Vitro Model of Hepatic Steatosis

et al. 2021

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Nonalcoholic fatty liver disease (NAFLD) is among the leading causes of end-stage liver disease. The impaired hepatic lipid metabolism in NAFLD is exhibited by dysregulated PPARα and SREBP-1c signaling pathways, which are central transcription factors associated with lipid degradation and de novo lipogenesis. Despite the growing prevalence of this disease, current pharmacological treatment options are unsatisfactory. Genistein, a soy isoflavone, has beneficial effects on lipid metabolism and may be a candidate for NAFLD treatment. In an in vitro model of hepatic steatosis, primary human hepatocytes (PHHs) were incubated with free fatty acids (FFAs) and different doses of genistein. Lipid accumulation and the cytotoxic effects of FFAs and genistein treatment were evaluated by colorimetric and enzymatic assays. Changes in lipid homeostasis were examined by RT-qPCR and Western blot analyses. PPARα protein expression was induced in steatotic PHHs, accompanied by an increase in CPT1L and ACSL1 mRNA. Genistein treatment increased PPARα protein expression only in control PHHs, while CPTL1 and ACSL1 were unchanged and PPARα mRNA was reduced. In steatotic PHHs, genistein reversed the increase in activated SREBP-1c protein. The model realistically reflected the molecular changes in hepatic steatosis. Genistein suppressed the activation of SREBP-1c in steatotic hepatocytes, but the genistein-mediated effects on PPARα were abolished by high hepatic lipid levels.

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Section: Discussionmentioning

confidence: 99%

Influence of Genistein on Hepatic Lipid Metabolism in an In Vitro Model of Hepatic Steatosis

et al. 2021

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“…Protected from chronic DOX in rats [190,229] and mice [185] in vivo. Augmented the cardioprotective effect of losartan against chronic DOX cardiotoxicity [230] Enhanced DOX anti-cancer effects in xenografts of leukemia P388 cells [185], liver cancer cells [231], 4T1 breast cancer cells [232,233] Reversed chemoresistance to DOX in hepatocellular carcinoma cells [202], breast cancer cells [200,212], prostate cancer cells [206], multidrug-resistant leukemia K562 cells [210] Enhanced chemotherapeutic effect of DOX against human breast cancer cells [195][196][197]199,234], human colorectal HT29 cancer cell line [208], neuroblastoma cells [235] Luteolin 79 [219] Protected against DOX-induced cardiomyocyte toxicity in vitro [188] Attenuated acute DOX-induced myocardial lipid peroxidation in vivo [236] Luteolin ( [240] Induced CYP1B1 gene expression [241,242] Protected from chronic DOX-induced cardiotoxicity in vivo [243,244] Protected from DOX-induced senescence in vascular smooth muscle cells [191] Potentiated the cytotoxic effect of DOX in MCF-7, MCF-7/ADR cells, MDA-MB-231 (breast), PC-3 (prostate), H460 (lung), and BxPC-3 (pancreas) cancer cells [213,[245][246][247]] Attenuated DOX-induced cytotoxicity in MCF-7 breast cancer cells in one study [248] Sensitized diffuse large cell lymphoma to CHOP (cyclophosphamide, DOX, vincristine, prednisone) chemotherapy in SCID tumor-bearing mice in vivo [2...…”

Section: Chemosensitizing Effects Of Cyp1b1 Inhibitorsmentioning

confidence: 99%

CYP1B1 as a therapeutic target in cardio-oncology

2020

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Cardiovascular complications have been frequently reported in cancer patients and survivors, mainly because of various cardiotoxic cancer treatments. Despite the known cardiovascular toxic effects of these treatments, they are still clinically used because of their effectiveness as anti-cancer agents. In this review, we discuss the growing body of evidence suggesting that inhibition of the cytochrome P450 1B1 enzyme (CYP1B1) can be a promising therapeutic strategy that has the potential to prevent cancer treatment-induced cardiovascular complications without reducing their anti-cancer effects. CYP1B1 is an extrahepatic enzyme that is expressed in cardiovascular tissues and overexpressed in different types of cancers. A growing body of evidence is demonstrating a detrimental role of CYP1B1 in both cardiovascular diseases and cancer, via perturbed metabolism of endogenous compounds, production of carcinogenic metabolites, DNA adduct formation, and generation of reactive oxygen species (ROS). Several chemotherapeutic agents have been shown to induce CYP1B1 in cardiovascular and cancer cells, possibly via activating the Aryl hydrocarbon Receptor (AhR), ROS generation, and inflammatory cytokines. Induction of CYP1B1 is detrimental in many ways. First, it can induce or exacerbate cancer treatment-induced cardiovascular complications. Second, it may lead to significant chemo/radio-resistance, undermining both the safety and effectiveness of cancer treatments. Therefore, numerous preclinical studies demonstrate that inhibition of CYP1B1 protects against chemotherapy-induced cardiotoxicity and prevents chemo- and radio-resistance. Most of these studies have utilized phytochemicals to inhibit CYP1B1. Since phytochemicals have multiple targets, future studies are needed to discern the specific contribution of CYP1B1 to the cardioprotective and chemo/radio-sensitizing effects of these phytochemicals.

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“…Genistein, which is one of the most important ingredients in soy isoflavone, is structurally similar with 17β-estradiol and is also known as a phytoestrogen. The beneficial effects of genistein on cardiovascular disease (Shi et al, 2019), cancer (Lepri et al, 2018), bone metabolic disease (Ye et al, 2018) and Alzheimer’s disease (Devi et al, 2017) have been extensively researched. And the safety of genistein intake was also verified in both animals and humans (Gilbert and Liu, 2013).…”

Section: Introductionmentioning

confidence: 99%

Maternal Genistein Intake Mitigates the Deleterious Effects of High-Fat Diet on Glucose and Lipid Metabolism and Modulates Gut Microbiota in Adult Life of Male Mice

et al. 2019

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Adverse early-life exposures program increased risk of chronic metabolic diseases in adulthood. However, the effects of genistein supplementation in early life on metabolic health in later life are largely unclear. Our objective was to investigate whether maternal genistein intake could mitigate the deleterious influence of a maternal high-fat diet on glucose and lipid metabolism in offspring and to explore the role of gut microbiota in mediating the transgenerational effects. C57BL/6 female mice were fed either a high-fat diet (HF), high-fat diet with genistein (0.6 g /kg diet) (HFG) or normal control diet (C) for 3 weeks before pregnancy and throughout pregnancy and lactation. The male offspring had ad libitum access to normal chow diet from weaning to 24 weeks of age. Then the content of inguinal subcutaneous adipose tissue (SAT) and epididymal visceral adipose tissue (VAT) were weighed. Glucose tolerance test (GTT), the level of serum insulin and lipid profiles were analyzed. The caecal contents were collected for 16S rDNA sequencing. The results showed that maternal genistein intake could significantly reduce blood glucose levels during GTT, fasting insulin levels, VAT mass and serum triglyceride levels as well as increase high-density lipoprotein cholesterol in adult male offspring. Significant decrease of germs from the Tenericutes phylum and enrichment of Rikenella as well as SCFA (short-chain fatty acid)-producing bacteria, including Alloprevotella, Odoribacter , and Clostridium XlVa , in offspring of genistein fed dams might play crucial roles in the improvement of glucose and lipid metabolism. Overall, early-life genistein intake attenuated the harmful effects of maternal HF on metabolism in adult offspring and the protective effects were associated with the alterations in gut microbiota, which provides new evidence and targets for mitigate the poor effects of adverse early-life exposures on metabolic health in later life.

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Genistein Affects Expression of Cytochrome P450 (CYP450) Genes in Hepatocellular Carcinoma (HEPG2/C3A) Cell Line

Cited by 17 publications

References 55 publications

Influence of Genistein on Hepatic Lipid Metabolism in an In Vitro Model of Hepatic Steatosis

Influence of Genistein on Hepatic Lipid Metabolism in an In Vitro Model of Hepatic Steatosis

CYP1B1 as a therapeutic target in cardio-oncology

Maternal Genistein Intake Mitigates the Deleterious Effects of High-Fat Diet on Glucose and Lipid Metabolism and Modulates Gut Microbiota in Adult Life of Male Mice

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