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

TY - JOUR

T1 - Transporter function and cyclic AMP turnover in normal colonic mucosa from patients with and without colorectal neoplasia

AU - Kleberg, Karen

AU - Jensen, Gerda Majgaard

AU - Christensen, Dan Ploug

AU - Lundh, Morten

AU - Grunnet, Lars Groth

AU - Knuhtsen, Svend

AU - Poulsen, Steen Seier

AU - Berner Hansen, Mark

AU - Bindslev, Niels

PY - 2012/6/26

Y1 - 2012/6/26

N2 - Background: 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.Methods: 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.Results: 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.Conclusions: 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.

AB - Background: 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.Methods: 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.Results: 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.Conclusions: 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.

KW - Aged

KW - Aged, 80 and over

KW - Basement Membrane

KW - Colon

KW - Colorectal Neoplasms

KW - Cyclic AMP

KW - Dinoprostone

KW - Endoplasmic Reticulum

KW - Female

KW - Goblet Cells

KW - Golgi Apparatus

KW - Humans

KW - Intestinal Mucosa

KW - Male

KW - Middle Aged

KW - Multidrug Resistance-Associated Proteins

KW - Organic Anion Transporters

U2 - 10.1186/1471-230X-12-78

DO - 10.1186/1471-230X-12-78

M3 - Journal article

C2 - 22734885

SN - 1471-230X

VL - 12

SP - 78

JO - B M C Gastroenterology

JF - B M C Gastroenterology

IS - 78

ER -