Transporter function and cyclic AMP turnover in normal colonic mucosa from patients with and without colorectal neoplasia

<p>Abstract</p> <p>Background</p> <p>The pathogenesis of colorectal neoplasia is still unresolved but has been associated with alterations in epithelial clearance of xenobiotics and metabolic waste products. The aim of this study was to functionally characterize the transport of cyclic nucleotides in colonic biopsies from patients with and without colorectal neoplasia.</p> <p>Methods</p> <p>Cyclic nucleotides were used as model substrates shared by some OATP- and ABC-transporters, which in part are responsible for clearance of metabolites and xenobiotics from the colonic epithelium. On colonic biopsies from patients with and without colorectal neoplasia, molecular transport was electrophysiologically registered in Ussing-chamber set-ups, mRNA level of selected transporters was quantified by rt-PCR, and subcellular location of transporters was determined by immunohistochemistry.</p> <p>Results</p> <p>Of four cyclic nucleotides, dibuturyl-cAMP induced the largest short circuit current in both patient groups. The induced short circuit current was significantly lower in neoplasia-patients (p = 0.024). The observed altered transport of dibuturyl-cAMP in neoplasia-patients could not be directly translated to an observed increased mRNA expression of OATP4A1 and OATP2B1 in neoplasia patients. All other examined transporters were expressed to similar extents in both patient groups.</p> <p>Conclusions</p> <p>OATP1C1, OATP4A1, OATP4C1 seem to be involved in the excretory system of human colon. ABCC4 is likely to be involved from an endoplasmic-Golgi complex and basolateral location in goblet cells. ABCC5 might be directly involved in the turnover of intracellular cAMP at the basolateral membrane of columnar epithelial cells, while OATP2B1 is indirectly related to the excretory system. Colorectal neoplasia is associated with lower transport or sensitivity to cyclic nucleotides and increased expression of OATP2B1 and OATP4A1 transporters, known to transport PGE₂.</p

Phytochemicals and colorectal cancer prevention-myth or reality?

Chemoprevention of colorectal cancer has been the focus of intensive research for more than two decades. Epidemiological evidence has shown a small, but significant association between fruit and vegetable intake and a reduction in colorectal cancer risk. In vitro and animal data have also demonstrated that many dietary phytochemicals have potent chemopreventive activities. However, in humans, single-agent compounds have yielded conflicting results. A key concept is that dietary phytochemicals exert beneficial effects at low concentrations when working in synergy with each other. As the gut microflora evolved in an environment rich in dietary fiber and phytochemicals, the rapid shift towards a Western diet creates an environment in which the gut is more vulnerable to carcinogens, genetic alterations and inflammation. As enforcing dietary interventions on large populations is not realistic, we believe future chemopreventive work should focus on delivering phytochemical mixtures that target the multiple molecular events involved in colorectal carcinogenesis