Quercetin and Dietary Lipids Alter the Cellular Redox Environment of the Colonocyte in the Promotion Stage of Colon Carcinogenesis.

Quercetin (Q), a water-soluble flavonoid that is ubiquitous to foods of plant origin is postulated to protect against colon cancer due to its antioxidant activity. In contrast, we have shown that a dietary combination of fish oil (FO; n-3 fatty acids) and pectin may protect against colon cancer by decreasing endogenous antioxidant enzyme activities leading to increased reactive oxygen species (ROS), an inducer of apoptosis. We hypothesized that adding an antioxidant to a FO diet may negate the beneficial effects of FO by counteracting FO effects on colonocyte redox status. To test this, we provided 40 rats with FO or CO (fiber = pectin) diets with Q being 0 or 0.45% of the diet for 10 wk. All rats were injected with azoxymethane (AOM) on d 21 and 28. Measurements included: aberrant crypt (AC) enumeration (colon cancer marker); apoptosis (TUNEL assay); catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx) activities; reduced and oxidized glutathione concentrations (GSH/GSSG); and oxidative DNA damage (8-OHdG adducts). AC numbers were lower in FO vs CO rats (p<0.0001), but tended to increase for FO diets containing Q (P<0.098). The apoptotic index was higher (p<0.0001) when Q was added to the FO and CO diets. Total SOD (lipid main effect, p=0.0136) and GPX activity (p=0.0025) was elevated in CO rats. CAT activity was higher (p=0.0204) in FO rats, however Q diminished this effect. GSH was not affected by diet; yet, GSSG accumulated (p=0.0554) in CO rats with Q as compared to CO rats without Q. The GSH/GSSG ratio was lower (p=0.0314) in CO rats than in FO rats. There was no difference in 8-OHdG adduct levels in FO vs CO rats, however, Q decreased 8-OHdG adducts in CO rats (p=0.0428). Despite increasing apoptosis, Q did not significantly lower AC formation. These data suggest that the distinct effects of the CO/Q and FO/Q combinations are functioning through different mechanisms to induce apoptosis. The long-term consequences of adding antioxidants such as Q to a diet thought to exert its anticancer effect through a pro-oxidant mechanism are unknown and deserve further study.