Flumequine enhances the in vivo mutagenicity of MeIQx in the mouse liver

Abstract

The combined effects of various carcinogens found in food products are a concern for human health. In the present study, the effects of flumequine (FL) on the in vivo mutagenicity of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) in the liver were investigated. Additionally, we attempted to clarify the underlying mechanisms through comprehensive gene analysis using a cDNA microarray. Male gpt delta mice were fed a diet of 0.03 % MeIQx, 0.4 % FL, or 0.03 % MeIQx + 0.4 % FL for 13 weeks. The effects of cotreatment with phenobarbital (PB) were also examined. Treatment with MeIQx alone increased gpt and Spi(-) mutant frequencies, and cotreatment with FL, but not with PB, further exacerbated these effects, despite the lack of in vivo genotoxicity in mice treated with FL alone. FL caused an increase in Cyp1a2 mRNA levels and a decrease in Ugt1b1 mRNA levels, suggesting that the enhancing effects of FL may be due in part to modification of MeIQx metabolism by FL. Moreover, FL induced an increase in hepatocyte proliferation accompanied by hepatocellular injury. Increases in the mRNA levels of genes encoding cytokines derived from Kupffer cells, such as Il1b and Tnf, and cell cycle-related genes, such as Ccnd1 and Ccne1, suggested that FL treatment increases compensatory cell proliferation. Thus, the present study clearly demonstrated the combined effects of 2 different types of carcinogens known as contaminants in foods.