In the present study, we investigated the effect of allyl isothiocyanate (AITC) on liver detoxification signaling pathway in 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary carcinogenesis. Mammary tumor was induced by a single dose of DMBA (25 mg/rat) injected subcutaneously near the mammary gland in Sprague-Dawley rats. DMBA-alone-treated rats show an increased synthesis of phase I detoxification enzymes, lipid peroxidative markers, liver marker enzymes, and lipid profiles whereas, depletion of phase II detoxification enzymes and antioxidants in rat liver tissues. Oral administration of AITC restored the levels of biochemical markers in DMBA-treated rats. Furthermore, histopathological results also confirmed that AITC protects DMBA-mediated hepatocellular damage. We also observed that AITC treatment significantly downregulates AhR and upregulates the expression of Nrf2 in DMBA-treated rats. The binding efficacy of AITC with AhR and Nrf2 analysis by molecular docking studies reveals that AITC has strong interaction with AhR and Nrf2 proteins through hydrogen and hydrophobic interactions. Thus, AITC prevents DMBA-induced mammary carcinogenesis via inhibition of phase I and induction of phase II detoxification enzymes by modulating AhR/Nrf2 signaling pathway.
Bisphenol-A (BPA) is a ubiquitous environmental chemical that produces adverse effect on reproduction system due to its potent estrogenic endocrine disruptive activity. The present study was aimed to investigate the monotonic dose effect of BPA on estrogen synthesis in female Sprague-Dawley rats. For this purpose, we administered three different doses of BPA (10, 50, 100 lg/ kg bw/day) into rats and analyzed various biochemical, hormonal, molecular and histological parameters. 10 lg BPA treated rats showed significantly decreased levels of phase I detoxification agents (CYP450, Cyt-b5). Overexpression of eNOS with decreased expression of StAR and steroidogenic enzymes (CYP11A1, aromatase) indicate decreased production of estrogen. Increased levels of serum gonadotropins (FSH, LH) and decreased levels of estradiol suggest mimetic action of BPA and its feedback inhibition. Increased body weight, lipid profile status of 10 lg BPA treated rats and histological analysis of ovary and mammary tissue support the study. Overall, our results suggest that BPA exerts its estrogen mimetic effects in a monotonic manner. Keywords Bisphenol-A Á Estrogen Á Ovary Á Mammary gland Abbreviation BPA Bisphenol-A TC Total cholesterol TG Triglycerides HDL-C High density lipoprotein-cholesterol TBARS Thiobarbituric acid substances GSH Reduced glutathione StAR Steroidogenic acute regulatory protein eNOS Endothelial nitric oxide synthase CYP11A1 Cytochrome P450 monooxygenase
Carcinogen induced mutation in somatic cells leads to genetic instability, which is considered as an important facet of carcinogenesis. Agents that inhibit DNA adduct formation, stimulate DNA repair mechanisms, and possess antioxidant functions are considered as antigenotoxic agents. Genistein, the major isoflavone of soy products, protects animals against experimentally induced mammary and prostate cancers. 7,12-Dimethylbenz[a]anthracene (DMBA), a potent site-specific carcinogen, induce mutations in DNA through its active metabolite, dihydrodiol epoxide, what is a crucial step in cancer initiation. The antigenotoxic effect of genistein against DMBA-induced genotoxicity has been investigated in the present study by analyzing the frequency of micronucleated polychromatic erythrocytes (MnPCEs) and chromosomal aberrations as cytogenetic end-points. The status of lipid peroxidation, antioxidants and detoxication agents were used as biochemical end-points to assess the antigenotoxic effect of genistein. Elevated MnPCEs frequency, marked chromosomal aberrations and enhanced status of lipid peroxidation, antioxidants and detoxication agents were observed in DMBA-treated animals. Oral pretreatment of genistein (20 mg/kg b.w.) for 5 days to DMBA-treated animals significantly reduced the frequency of micronucleus formation and chromosomal abnormalities as well as reversed the status of biochemical variables. Our results suggest that genistein has potent antigenotoxic effect against DMBA-induced genotoxicity.
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