-We previously found that administration of ascorbic acid (AA) enhances the liver tumorpromoting activity of kojic acid (KA) in mice. To examine the reproducibility of these results in rats and the underlying mechanism of this effect, we employed a two-stage liver carcinogenesis model using male F344 rats. Two weeks after initiation with diethylnitrosamine (DEN), the animals received a diet containing 2% KA and drinking water with or without 5,000 ppm AA for a period of 7 weeks. A DENalone group was also established as a control. One week after the commencement of the administration, the animals were subjected to two-thirds partial hepatectomy. At the end of the experiment, the livers were analyzed immunohistochemically, and the mRNA expression level and extent of lipid peroxidation were measured. AA treatment enhanced the KA-induced tumor-promoting activity in terms of the number and area of liver cell foci that were positive for glutathione-S-transferase placental form. AA coadministration increased the number of hepatocytes positive for proliferating cell nuclear antigen and inversely decreased the number of TUNEL-positive cells. However, the increased level of thiobarbituric acid reactive substances resulting from KA treatment was suppressed by coadministration of AA. Gene expression analyses using low-density microarrays and real-time RT-PCR showed that coadministration of AA resulted in upregulation of genes related to cell proliferation and downregulation of those involved in apoptosis and/or cell cycle arrest. These results indicate that the concerted effects of AA on cell proliferation and apoptosis/cell cycle arrest probably through its antioxidant activity are involved in this enhancement.
To evaluate the carcinogenicity of troglitazone in rasH2 mice, 7-week-old male and female rasH2 mice were fed a diet containing 0, 3,000 or 6,000 ppm troglitazone for 26 weeks. An increased tendency in the incidence of vascular tumors was observed in females of the 6,000 ppm group. The preliminary analysis using a high-density oligonucleotide microarray on a splenic hemangiosarcoma of a high dose female that could be obtained as a fresh sample showed that several genes related to the ras/MAPK pathway activation, angiogenesis, cell cycle and cell multiplication were up-regulated. In addition, most of the genes up-regulated were confirmed by the reverse transcriptase-polymerase chain reaction (RT-PCR). These results may suggest that the carcinogenic susceptibility of rasH2 mice to troglitazone is relatively low and up-regulations of the ras/MAPK pathway and angiogenesis-related genes are probably involved in the production of splenic hemangiosarcomas in rasH2 mice given troglitazone.
ABSTRACT. To examine the tumor modification activity of kojic acid (KA) by sodium ascorbic acid (AA), 5-week-old male ICR mice were administered intraperitoneally with N-diethylnitrosamine (DEN) as an initiation treatment. Two weeks after the initiation treatment, animals were fed basal diet containing 0 (Group 1: DEN alone) or 3% KA (Group 3: DEN+KA), drinking water containing 5,000 ppm AA (Group 2: DEN+AA) or 3% KA and 5,000 ppm AA (Group 4: DEN+KA+AA) for 6 weeks. One week after the administration of KA and/or AA, all mice were subjected to two-thirds partial hepatectomy. At the end of the experimental period, all surviving mice were sacrificed and removed the liver. The liver weights of the Groups 3 and 4 were significantly increased, and the number of proliferating cell nuclear antigen positive hepatocytes and the gene expressions of Ccnc, Ccnd1, Ercc and Cyp7a1 were significantly increased in the Group 4, as compared to the Group 1. These results of the present study suggest that AA enhances the hepatocellular proliferative activity of KA in mice. KEY WORDS: ascorbic acid, hepatocarcinogenesis, kojic acid, mouse.J. Vet. Med. Sci. 69(9): 899-908, 2007 Kojic acid (KA; 5-hydroxy-2(hydroxymethyl)-4-pyrone) is a secondary metabolic product of various species of Aspergillus and Penicillium [23]. It is known that this acid inhibits polyphenol oxidase (tyrosinase) in mushrooms, potatoes, apples and crustaceans [41]. Since polyphenol oxidase catalyzes the conversion of tyrosine to melanin via 3,4-dihydroxyphenylalanine and dopaquinone [21], KA has been used as an inhibitor of polyphenol oxidase in food additives for preventing enzymatic browning of raw crabs and shrimps. In addition, because of its excellent skin whitening properties [35] and inhibitory actions on human melanocyte tyrosinase [28], KA has been applied as a cosmetic agent for the purpose of skin lightening.It has been reported that hepatocellular tumors were induced in B6C3F1 mice that were fed diet containing 3% KA for 20 months [14]. In another study, diet containing 0, 1.5 or 3% KA was administered to heterozygous p53-deficient mice of the CBA strain [p53 (+/-) mice] and their wild-type littermates [p53 (+/+) mice] for 26 weeks [50]. In the study, the incidences of hepatocellular adenomas as well as altered hepatocellular foci were increased in p53 (+/-) and p53 (+/+) mice of KA-treated groups with and/or without initiation, as compared to those in the untreated control mice. In our previous confirmation study using CBA wildtype mice, the incidence of proliferative lesions was significantly increased in the liver of mice that were fed diet containing 1% KA for 26 weeks [51]. In addition, it has recently been reported that a 20-week dietary administration of 2% KA increases the number and area of glutathione Stransferase placental (GST-P) form positive foci in the liver of F344 rats [49]. These findings suggest the hepatocarcinogenic potential of KA in the liver of rodent species.With regard to the genotoxicity of KA, several in vitro genotoxici...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.