Transporter function and cyclic AMP turnover in normal colonic mucosa from patients with and without colorectal neoplasia.
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 PGE(2).
Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. kkh@farma.ku.dk
Karen
K
Kleberg
Gerda Majgaard
GM
Jensen
Dan Ploug
DP
Christensen
Morten
M
Lundh
Lars Groth
LG
Grunnet
Svend
S
Knuhtsen
Steen Seier
SS
Poulsen
Mark Berner
MB
Hansen
Niels
N
Bindslev
D000368:Aged; D000369:Aged, 80 and over; D001485:Basement Membrane / Q000378:metabolism; D003106:Colon / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology; D000242:Cyclic AMP / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005260:Female; D020397:Goblet Cells / Q000378:metabolism; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D027361:Organic Anion Transporters / Q000378:metabolism*
D000242:Cyclic AMP; D015232:Dinoprostone; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D027361:Organic Anion Transporters; C073492:ABCC4 protein, human; C120809:ABCC5 protein, human; C450859:SLCO2B1 protein, human; C498174:SLCO4A1 protein, human