Some fish species are being used as supplemental animals for carcinogenicity studies; however, basic research is required to determine if mechanisms of carcinogenesis in these teleosts reflect the carcinogenic process in mammals. The object of this study was to compare 7,12-dimethylbenz[a]anthracene (DMBA)metabolism and DNA adduct formation in liver cells from the teleost, Japanese medaka, with that in mouse embryo fibroblasts (MEF). Cells were isolated by enzymatic digestion and maintained in monolayer culture. Following exposure to DMBA, culture medium was removed and analyzed by high pressure liquid chromatography for phase I DMBA metabolites. The rate of formation of phase I metabolites was significantly lower in medaka liver cells (MLC) than in MEF. Differences in the types of phase I metabolites found were also apparent: DMBA 3,4-dihydrodiol (important for mammalian carcinogenesis) was barely detectable, in MLC, but was a significant metabolite in MEF; DMBA 5,6-diol and hydroxymethyl DMBA were major metabolites in MLC, but were minor metabolites in MEF. 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin pretreatment resulted in 5 to 6 fold increases in formation of total DMBA phase I metabolites in both types of cells. Furthermore, 3H-DMBA-DNA adducts were formed at lower levels in MLC than in MEF, and C 18 chromatography demonstrated the DNA-adducts formed in MLC were much more polar than most of the adducts formed in MEF. These findings indicate significant differences in DMBA metabolism and adduct formation between MLC and MEF. Although DMBA is a potent carcinogen in both mammalian and teleost systems, the mechanisms that bring about carcinogenesis may be quite different.
Animal-studies; Laboratory-animals; Statistical-analysis; Analytical-methods; Analytical-chemistry; Exposure-assessment; Toxicology; Toxins; Toxic-materials; Metabolites; Metabolism; DNA-adducts; DNA-damage; Liver; Liver-cancer; Liver-cells; Liver-damage; Liver-disorders; Liver-function; Carcinogens; Carcinogenicity; Cancer
The Toxicologist. Society of Toxicology 38th Annual Meeting, March 14-18, 1999, New Orleans, Louisiana