Roles of carbonic anhydrase isozymes in the pathogenesis of pancreatitis and pancreas cancer.

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We successfully obtained novel cDNA clones of two CA isozymes (CA VB and XIV) and two CA-related proteins (CA-RP X and XI). Biochemical analysis indicated that CA VB was a mitochondrial isozyme and CA XIV was a transmembrane isozyme. Since CA-RP X and XI lack at least one of three zinc-binding histidine residues which are critical for the CA catalytic activity, they were though to be acatalytic proteins. mRNA expressions of CA II, IV, VB, VI, XI, XII, CA-RP X, and XI were identified in the human pancreas. Immunohistochemical analyzes with monoclonal antibodies to three CA-RPs showed positive staining of only CA-RP VIII in pancreatic exocrine cells. The results obtained herein and in previous studies indicate the significant expression of CA II, IV, IS, and XII in ductal epithelial cells of the pancreas.Based on the results described above, we studied roles of CA II, IV, IX and XII as a target antigen in the pathogenesis of autoimmune pancreatitis (AIP). Western blot analyzes were employed to identify serum antibody in patients with idiopathic chronic pancreatitis (ICP, n=80) and normal controls (NC, n=30). In result, serum antibodies to CA II and IV were seen in 30 % and 5 % in ICP and 10 % and 3 % in NC, respectively. Serum antibodies to CA IX and XII were not observed in all ICP patients and NC. CA II is widely distributed in almost of all tissue types but CA IV expression is relatively limited in ductal epethelial cells of exocrine organs. In consideration with the fact that AIP and its complications (Sjogren's syndrome and primary sclerosing cholangitis) pathologically showed "ductulitis", our results suggest that CA IV is a candidate antigen playing an important role in the pathogenesis of AIP.