metabolism and carcinogenicity of aflatoxins
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Publication
Journal: Journal of the National Cancer Institute
August/26/1981
Abstract
Aflatoxicol (AFL), a metabolite of aflatoxin B1 (AFB1), is formed in vitro by liver preparations from several species including humans. A positive correlation appears to exist between the sensitivity of a species to AFB1 and the species ability to metabolize AFB1 to AFL. Conversion of AFB1 to AFL is, therefore, a questionable detoxification step. The carcinogenicity of a diastereoisomeric mixture of AFL, prepared chemically from AFB1, was compared to AFB1 by tumor incidences being determined in 4 groups of 20 weanling male F344 rats fed either a negative control diet with no aflatoxin, a positive 50-ppb AFB1 control diet, a 50-ppb AFL diet, or a 200-ppb AFL diet for 1 year and then killed at the end of the 2d year. The respective hepatocellular carcinoma incidences were 0, 40, 20, and 70%, demonstrating that AFL is carcinogenic in the rat. The data show that a diastereoisomeric mixture of AFL is one-half as carcinogenic as AFB1, and the dose response appeared nearly linear in that a fourfold increase in dose produced a 3.5-fold increase in tumor incidence. The data did not establish unequivocally that AFL is a proximate carcinogen, but metabolism of AFB1 to AFL should not be considered an efficient detoxification reaction.
Publication
Journal: National Cancer Institute monograph
August/29/1984
Abstract
Hepatocytes were prepared from rainbow trout by perfusion in situ with collagenase and hyaluronidase. Preparations normally showed high initial viability (95 +/- 5% dye exclusion, 92 +/- 5% lactate dehydrogenase retention) and gradually decreased in viability and glutathione concentration over 5 hours. Cellular metabolism of aflatoxin B1 (AFB1), a potent hepatocarcinogen, was characterized by an investigation of the following parameters: kinetics of AFB1 metabolism and DNA adduct formation, dose response, viabilities of detoxication and activation pathways with time, influence of organic solvents, and effect of variation in cell concentration. The AFB1 metabolites and DNA adducts were resolved and quantitated by high-performance liquid chromatography. From these results a standardized assay procedure was derived which we used to examine AFB1 metabolism and DNA adduct formation in hepatocytes from fish fed dietary substances known to alter the carcinogenic response to this mycotoxin. Dietary beta-naphthoflavone, which strongly inhibits AFB1 carcinogenesis in rainbow trout, dramatically and reproducibly altered AFB1 binding and metabolism in isolated hepatocytes. Overall rate of AFB1 metabolism and rates of detoxication reactions increased, whereas DNA binding decreased. Dietary cyclopropenoid fatty acids, powerful synergists and promoters of AFB1 carcinogenesis in trout, also repressed AFB1-DNA binding. Both dietary factors appeared to depress initial DNA damage by AFB1 but operated through different metabolic pathways to do so.
Publication
Journal: Carcinogenesis
February/23/1984
Abstract
Isolated hepatocytes from rainbow trout readily activated aflatoxin B1 (AFB1) to mutagens detectable by S. typhimurium TA 98. Characterization studies demonstrated that activation efficiency was essentially linear with respect to hepatocyte concentration (5 X 10(5)-2 X 10(7) cell/ml) and AFB1 dose (0-10 micrograms/ml). This system was employed to assess possible differences in AFB1 activation in hepatocytes from rainbow trout and coho salmon, two species which have been shown in in vivo studies to differ widely in sensitivity to AFB1 carcinogenesis. Activation efficiency was approximately three times greater in trout hepatocytes compared with salmon hepatocytes. This difference was more marked when S20 liver fractions from the two species were used. Analysis of unbound [3H]AFB1 metabolites performed on supernatants of hepatocyte incubations revealed that under the normal conditions of assay, addition of bacteria does not perturb the various pathways of AFB1 metabolism within hepatocytes. These results support other studies which suggest that the greater sensitivity of trout to AFB1 carcinogenicity resides largely in increased initial DNA damage, compared with coho salmon.