Detection of initiating potential of non-genotoxic carcinogens in a two-stage hepatocarcinogenesis study in rats

Abstract

-We previously reported a toxicogenomics-based prediction model for hepatocarcinogens in which the expression patterns of signature genes following repeated doses of either genotoxic or nongenotoxic compounds were similar. Based on the results of our prediction model, we hypothesized that repeated doses of non-genotoxic carcinogens might have initiating potential. Here, we conducted a twostage hepatocarcinogenesis study in rats exposed to the initiating agent nitrosodiethylamine (DEN), and hepatotoxic compounds thioacetamide (TAA), methapyrilene (MP) and acetaminophen (APAP) for 1-2 weeks followed by the liver tumor promoter phenobarbital (PB). The duration of initial treatment was determined based on positive results from our prediction model. Combined treatment of 3 or 30 mg/kg of genotoxic DEN and PB induced marked increases in altered hepatocellular foci and a DEN dose-dependent increase in the number and area of glutathione S-transferase-placental form (GST-P)-positive foci. A low number of altered hepatocellular foci were also observed in rats treated with TAA at a dose of 45 mg/kg. MP at a dose of 100 mg/kg induced a very low number of foci, but APAP did not. Hierarchical clustering analysis using gene expression data revealed that 2-week treatment with TAA at a dose of 30 mg/kg and MP at 45 mg/kg induced specific expression of DNA damage-related genes, similar to 1-week treatment with DEN at a dose of 30 mg/kg. These results suggest that TAA and MP induce DNA damage, which partially supports our hypothesis. Although this study does not indicate whether tumor growth in response to these compounds can be assessed in this model, our results suggest that cumulative treatment with nongenotoxic TAA might have initiating potential in the liver.

Fagonia indica Repairs Hepatic Damage through Expression Regulation of Toll-Like Receptors in a Liver Injury Model

“…Serum biochemistry is an important parameter for the diagnosis of liver diseases and for the assessment of the degree of liver damage [ 57 ]. Plasma levels of liver enzymes such as ALT, AST, and ALP, which are known hallmarks of TAA toxicity, are increased [ 58 , 59 ]. Similar results were observed in the present study where the TAA group showed considerable elevations in serum levels of ALT, AST, ALP, total proteins, and globulin compared to the control in accordance with previous findings [ 60 ].…”

Disruption of spindle checkpoint function in rats following 28 days of repeated administration of renal carcinogens

“…These results suggest that it is difficult to find the relationship between the potential to induce spindle checkpoint dysfunction and genotoxic potential of renal carcinogens. Of note, we have shown disruption of spindle checkpoint function in liver cells after repeated 28-day administration of non-genotoxic hepatocarcinogens, i.e., thioacetamide and methapyrilene, in rats (Kimura et al, 2015a(Kimura et al, , 2015bOmura et al, 2014). These results suggest that spindle checkpoint dysfunction may be caused by carcinogens without relationship to their genotoxic potential.…”

Animal models as a tool in hepatocellular carcinoma research: A Review

“…94,95 Despite the fact that some of the chemical hepatocarcinogenesis events remain uncertain, the multistage process-Initiation ⇒ Promotion ⇒ Progression-is an accepted theory. 72,96 Its complexity can only be studied in vivo involving all aspects of exposure and target organ biology. 96 Regarding DEN, if it is injected into younger mice (less than 2 weeks), it acts as a complete carcinogen, due to higher hepatocyte proliferation rates in the juvenile.…”