Suppressive effect of enzymatically modified isoquercitrin on phenobarbital-induced liver tumor promotion in rats

Abstract

To investigate the effect of enzymatically modified isoquercitrin (EMIQ) on hepatocellular tumor promotion induced by phenobarbital (PB), male rats were administered a single intraperitoneal injection of 200 mg/kg N-diethylnitrosamine (DEN) and then fed with a diet containing PB (500 ppm) for 8 weeks, with or without EMIQ (2,000 ppm) in the drinking water. One week after PB administration, rats underwent a two-thirds partial hepatectomy. The PB-induced increase in the number and area of glutathione S-transferase placental form-positive foci and the proliferating cell nuclear antigen-positive ratio was significantly suppressed by EMIQ. Real-time reverse transcription-polymerase chain reaction analysis revealed increases in mRNA expression levels of Cyp2b2 and Mrp2 in the DEN-PB and DEN-PB-EMIQ groups compared with the DEN-alone group, while the level of Mrp2 decreased in the DEN-PB-EMIQ group compared with the DEN-PB group. There were no significant changes in microsomal reactive oxygen species (ROS) production and oxidative stress markers between the DEN-PB and DEN-PB-EMIQ groups. Immunohistochemically, the constitutive active/androstane receptor (CAR) in the DEN-PB group was clearly localized in the nuclei, but its immunoreactive intensity was decreased in the DEN-PB-EMIQ group. These results indicate that EMIQ suppressed the liver tumor-promoting activity of PB by inhibiting nuclear translocation of CAR, and not by suppression of oxidative stress.

Liver tumor promoting effect of orphenadrine in rats and its possible mechanism of action including CAR activation and oxidative stress

“…These results suggest that ORPH mainly induces CYP2B during the metabolic process in the rat liver. It has been reported that chemicals that induce CYP2B and have a hepatic tumor promoting activity produce ROS during the metabolism of these, and the resulting oxidative stress stimulates the tumor promoting effect in the rat liver (Dewa et al, 2009;Morita et al, 2011). In the present study, ROS production was increased in rats given 750 ppm ORPH or more, and the level of TBARS and 8-OHdG was increased in the DEN-High ORPH group.…”

“…The nuclear translocation of CAR induced by PB stimulates the expression of various genes that enhance hepatic tumor promotion (Deguchi et al, 2009;Kawamoto et al, 1999). In addition, it has been shown that microsomal ROS production and production of thiobarbituric acid-reactive substances (TBARS) and are induced by PB with increasing the Cyp2b (Morita et al, 2011). Taking these facts into account, we hypothesize that ORPH has a liver tumor-promoting activity similar to the activity of PB.…”

Review of anticancer mechanisms of isoquercitin

“…The phenobarbital increased oxidative stress with the formation of ROS and activation of CAR. The group treated with EMIQ showed a significant decrease in oxidative stress markers in addition to inhibition of MAPK and CAR pathways, confirming the antioxidant and antiproliferative actions of this molecule [88,89] . A study investigated the effects of enzymatically modified IQ on preneoplastic liver cell lesions induced by thioacetamide promotion in a hepatocarcinogenesis rat model.…”

“…Enzymatically modified IQ suppressed the liver tumorpromoting activity of phenobarbital by inhibiting nuclear translocation of constitutive active/androstane receptor (CAR), and not by suppressing oxidative stress in rats. Morita et al [88] investigated the action of EMIQ in an experimental model of liver tumor induced by phenobarbital, a sedative and antiepileptic drug. The phenobarbital increased oxidative stress with the formation of ROS and activation of CAR.…”

“…Numerous extra cellular stimuli activate MAPK pathways, generating a chain of reactions leading to intracellular remodeling and biochemical cascades. These pathways have been associated with several diseases including cancer [88,89,92] . Mutations in the MLK3 gene were first described in gastric and colorectal cancer [94] and the oncogenic effect was related to invasive induction of tumor cells.…”