Free Radical Generating Mechanisms in the Colon: Their Role in the Induction and Promotion of Colorectal Cancer?

Abstract

A hypothesis is presented to account for the dietary induction and promotion of colorectal cancer. The principal agents are the secondary bile acids, lithocholic and deoxycholic acids, the vitamin K group and ferrous iron complexes. These metabolites may interact to subvert the normal free radical generating mechanisms involved in mucosal defence. Diets high in fat and red meat and low in fibre support a Bacteroides-dominated colonic microflora, which both synthesises and utilises vitamin K2 isoprenalogues or menaquinones as enzyme co-factors. Iron(II) complexes such as haemin from the breakdown of dietary haemoglobin and myoglobin also serve as growth factors for these bacteria and provide a rich source of haem-iron for intestinal uptake. Biliary secretion is stimulated by dietary fat and bile acids are essential for the intestinal uptake of vitamin K and possibly of iron complexes such as haemin. In the mature colonocyte, vitamin K and haemin may initiate redox cycling reactions which liberate superoxide (O−2 ·). Bile acids can activate the membrane bound phospholipase to liberate arachidonate and diacylglycerol. This leads in turn to the production of more O−2 · which can enter the microcirculation and acts as a potent chemoattractant for the neutrophils that line the lamina propria. The released diacylglycerol can activate protein kinase C in the neutrophil membrane to switch on the respiratory burst oxidase system generating yet more O−2 · and may stimulate the proliferation of transformed stem cells by a similar protein kinase C mediated mechanism. The additive effects of bile acids, vitamin K and iron(II) in oxygen radical generation may overcome the antioxidant defence mechanisms of the stem cell leading ultimately to semiquinone and hydroxyl radical mediated DNA damage and tumour induction.