The main objective is to test the hypothesis that quercetin, a naturally-occurring edible plant flavonol, produces small and large bowel, hepatic, and urinary bladder neoplasms in rats, and that its oncogenic activity is related to dietary manganese (Mn) and/or selenium (Se) levels. Quercetin is the most common plant flavonol, occurring as a glycone, with ubiquitous distribution in widely varying concentrations in vegetables and fruits eaten by humans. It is estimated that humans consume about one gm per day of flavonols. We first demonstrated the mutagenicity of quercetin for Salmonella typhimurium, an observation confirmed by others. Quercetin mutagenicity is dependent on trace element concentrations, and the presence of certain co-factors and other enzymes. Oncogenicity studies of quercetin resulted in divergent results. We have produced intestinal, vesical, and more recently hepatic tumors in high incidence in rats fed quercetin; others have not observed such effects. Comparative diet analyses suggest that positive results with quercetin have been obtained in rats fed diets containing low levels of Mn and Se. We suggest that quercetin glycones (non-mutagenic) are hydrolyzed by intestinal bacteria, or intestinal mucosa and other tissues to aglycones that in turn are converted into proximate molecular carcinogenic species, most probably at their site of formation. Though the active molecular species of quercetin responsible for mutagenic effects have not been identified, structure-activity studies suggest that they are unstable electrophilic flavonol-quinones or hydroperoxides. Tissue levels of these quercetin oxidation products could be regulated by Mn-dependent superoxide dismutase and/or Se-dependent peroxidase. Inadequate availability of Mn or Se impairs these enzymes, and thus might permit formation of electrophilic intermediates from quercetin. We propose to feed quercetin in defined diets at levels of 0.1% and 2% to 4-week old Fischer 344 rats. In one study, dietary levels of Mn will be 50, 10 and 1 ppm; and in a second study dietary levels of Se will be 100, 40 and 15 ppb. Rats will be killed at 2 years with complete histopathologic evaluation. Water and diet levels of Mn and Se will be measured by atomic absorption spectrophotometry. Dietary levels of quercetin will be measured by HPLC. These data should permit an evaluation of the carinogenicity of quercetin and interrelationships with trace minerals.
| Busch, D B; Bryan, G T (1987) Presence and measurement of sample histidine in the Ames test: quantification and possible elimination of a source of false-positive mutagenicity test results. Environ Mol Mutagen 10:397-410 |
| Busch, D B; Hatcher, J F; Bryan, G T (1986) Urine recovery experiments with quercetin and other mutagens using the Ames test. Environ Mutagen 8:393-9 |
| Busch, D B; Archer, J; Amos, E A et al. (1986) A protocol for the combined biochemical and serological identification of the Ames mutagen tester strains as Salmonella typhimurium. Environ Mutagen 8:741-51 |
| Hatcher, J F; Bryan, G T (1985) Factors affecting the mutagenic activity of quercetin for Salmonella typhimurium TA98: metal ions, antioxidants and pH. Mutat Res 148:13-23 |
