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Clin Exp Pharmacol Physiol. 2019 Sep 28. doi: 10.1111/1440-1681.13184. [Epub ahead of print]

Quinazolinone derivative BNUA-3 ameliorated [NDEA+2-AAF]- induced liver carcinogenesis in SD rats by modulating AhR-CYP1B1-Nrf2-Keap1 pathway.

Author information

1
Division of Advanced Pharmacology, Department of Pharmaceutical Sciences & Technology, Birla Institute of Technology, Mesra, Ranchi, 835215.
2
Department of Pharmaceutical Sciences & Technology, Birla Institute of Technology, Mesra, Ranchi - 835215, India.
3
Department of Oncology & Metabolism, University of Sheffield, Medical School, Beech Hill Road, Sheffield, S10 2RX, United Kingdom.

Abstract

Cytochrome P450 1B1, considered as one of the novel chemotherapeutic targets involved in cancer prevention and therapy is also associated with the conversion of procarcinogens into their active metabolites. The aryl hydrocarbon receptor (AhR) is responsible for mediating different biological responses to a wide variety of environmental pollutants and also causes transcriptional activation of cytochrome P450 enzymes including CYP1B1 and thus plays a pivotal role for initiating cancer and its progression. On the other hand, active carcinogenic metabolites and reactive oxygen species mediated stress alter different molecular signaling pathways and gene expressions. Quinazoline derivatives are recognized for their diversified biological activities including anticancer properties. The current study was designed for evaluation of chemotherapeutic efficacy of a synthetic quinazolinone derivative BNUA-3 against hepatocellular cancer in Sprague-Dawley (SD) rats. A detailed in-vivo analysis was performed by administrating BNUA-3 (15, 30 mg/kg b.w. for 28 days, i.p.) in N-Nitrosodiethylamine + 2-Acetylaminofluorene induced partially hepatectomized liver cancer in SD rats. This was followed by morphological evaluations, biochemical estimations and analysis of different mRNA and protein expressions. The results demonstrated the potency of BNUA-3 in efficient restoration of the altered morphology of liver, its protective effect against lipid peroxidation, enzymic and nonenzymic antioxidants levels in liver tissue which was disrupted after cancer induction. The study also demonstrated downregulation of AhR, CYP1B1 and Keap1 expressions with subsequent augmentation of protective Nrf2, HO-1, NQO1 and GSTA1 expressions thus, revealing the chemotherapeutic potency of BNUA-3 in inhibiting liver carcinogenesis through AhR/CYP1B1/Nrf2/Keap1 pathway.

KEYWORDS:

AhR; CYP1B1; FESEM; Hepatocellular carcinogenesis; NDEA+ 2-AAF; SD rats

PMID:
31563143
DOI:
10.1111/1440-1681.13184

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