Chemoprevention studies with Pacific foodstuffs: effects on xenobiotic metabolising enzymes and cytotoxicity

Abstract

The aims of this thesis were to examine:(1) the effects of acute and chronic dietary exposure of the pro-carcinogen, IQ on the expression and activity of xenobiotic metabolising enzymes; (2) the ability of foodstuffs chronically (individually and in combination with the dietary pro-carcinogen IQ) to alter the xenobiotic metabolising enzymes; (3) whether tissue-specific effects of the foodstuffs on XME could explain pathological results; and (4) whether any isolated fraction of the foodstuffs acted directly as a toxicant or stimulated cell growth in vitro. For the chronic study, male Fischer 344 rats were fed defined AIN-76A diet ± 10% foodstuff (taro, kumara, pineapple, or coconut), with or without IQ (300ppm for 52 weeks). In the acute study, male Fischer 344 rats were fed defined AIN-76A diet and gavaged with IQ (20 mg.kg-1, 3 days). Pathology was observed and changes in enzyme activities and expression examined. Simple fractionation of the foodstuffs was also performed and their effects on cell viability and enzyme expression were investigated in vitro in freshly isolated rat hepatocytes and immortal human HT29 and P388 cells. In the liver, acute exposure to IQ affected enzymes consistent with complex xenobiotic response element / glucocorticoid response element activation, whereas chronic exposure was consistent with activation of the antioxidant response element. No pattern of enzyme change was obvious in other organs. Inclusion of South Pacific foodstuffs in the diet at 10% had a marked effect on enzyme activity in the liver and lung, although there was no consistent pattern for enzyme changes for a particular enzyme or foodstuff. Enzyme activity in the colon was below the level of detection. There was a complex response when IQ was included with the foodstuffs, which did not resemble the response to either IQ or the foodstuff alone. Fractionation of foodstuffs and in vitro cell-based work did not reveal the presence of compounds in the foodstuffs that explained the complex changes in pathology or XME observed in vivo. The interaction between foodstuffs and IQ in the body was complicated. This may be explained by the presence of many compounds within the foodstuffs that have additive, synergistic, or inhibitory actions on many pathways in the body and underlines the complexity of using whole foodstuffs, rather than a single, purified constituent, in chemoprevention studies.