Antioxidant enzymatically modified isoquercitrin or melatonin supplementation reduces oxidative stress-mediated hepatocellular tumor promotion of oxfendazole in rats

Abstract

To clarify whether enzymatically modified isoquercitrin (EMIQ) or melatonin (MLT) supplementation reduces oxidative stress-mediated hepatocellular tumor-promoting effect of oxfendazole (OX), a benzimidazole anthelmintic, male rats were administered a single intraperitoneal injection of N-diethylnitrosamine (DEN) and were fed a diet containing OX (500 ppm) for 10 weeks with or without EMIQ (2,000 ppm) or MLT (100 ppm) in the drinking water after DEN initiation. One week after the commencement of the administration of OX, rats were subjected to two-thirds of partial hepatectomy. The number of GST-P-positive foci promoted by OX was significantly inhibited by the combined antioxidant EMIQ or MLT administration, and the area of GST-P-positive foci was inhibited by the administration of MLT. Real-time RT-PCR analysis revealed decreases in mRNA expression levels of cytochrome P450, family 2, subfamily b, polypeptide 2 (Cyp2b2) and malic enzyme 1 (Me1) in the DEN-OX-EMIQ and DEN-OX-MLT groups and decreases in mRNA expression levels of Cyp1a1 and aldo-keto reductase family 7, member A3 (Akr7a3) in the DEN-OX-MLT group compared to those in the DEN-OX group. In in vitro ROS production assay, inhibited production of NADPH-dependent ROS was observed by the treatment with EMIQ or MLT. These results suggest that coadministration of EMIQ or MLT suppresses the hepatocellular tumor-promoting activity of OX in rats through the decrease in ROS production by the activation of CYPs.

Flavonoids from tartary buckwheat induce G<sub>2</sub>/M cell cycle arrest and apoptosis in human hepatoma HepG2 cells

“…There are many kinds of flavonoids found ubiquitously in plants and the biological activities of flavonoids cover a very broad spectrum including antioxidation, antiviral, antiinflammatory, prevention of cardiovascular diseases, and anticancer properties [3][4][5]. Some researchers suggested that flavonoids are effective antioxidants that have a strong inhibitory effect on the proliferation of several human cancer cell lines [6,7].…”

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“…Significant increase of total anti-oxidative status (TAS) level in plasma of multiple sclerosis (MS) patients has been observed with melatonin supplementation 95 . In animal models, melatonin has been demonstrated to prevent the damage to mitochondrial and nuclear DNA by carcinogens [97][98][99][100][101] .…”

Liver tumor promoting effect of etofenprox in rats and its possible mechanism of action

“…Imaoka et al (2004) reported that the induction of CYP2B1 by PB increased ROS production and also induced genomic DNA oxidation that may contribute to the tumor promotion of PB. In addition, OX, which has a capability to induce CYP1A and CYP2B, induces ROS generation resulting in oxidative DNA damage and liver tumor promotion in rats (Dewa et al, 2009;Nishimura et al, 2010). Therefore, chemicals inducing CYP2B are generally considered to be liver tumor promoters in rats.…”