Ethanol/lipid metabolism, dysfunction of ion transport, and pathogenesis of alcoholic pancreatitis

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1. Mutations and polymorphisms (TG repeats, poly T, M470V, Q1352H, R1453W) of CFTR (cystic fibrosis transmembrane conductance regulator) were examined in Japanese patients with chronic pancreatitis. None of the cystic fibrosis-causing mutations were detected. Frequency of the genotype TG(12/12) was higher in alcoholic pancreatitis. Frequency of the genotype V470/V470 was higher in idiopathic pancreatitis.2. To estimate CFTR Cl^- channel function, we established "finger sweat chloride test" to measure Cl^- concentration in insensible sweat, which sweat is collected by holding a small tube containing 100 μl water with the thumb and the sweat rate is measured by a perspiration meter. The Cl^- content in the sample is measured by capillary electrophoresis or more easily by a highly sensitive electrode.3. The activity of Na^+-H^+ exchange (NHE) in the apical membrane was examined in luminally-microperfused interlobular pancreatic duct segments isolated from ΔF mice, a cystic fibrosis model. The apical NHE activity significantly increased in ΔF/ΔF ducts, which may cause pH decrease of pancreatic juice.4. Effects of a series of short-chain alcohols (methanol, ethanol, propanol, and butanol) on cAMP-stimulated fluid secretion and intracellular Ca^<2+> concentration were examined in interlobular pancreatic duct segments isolated from guinea-pig. Methanol and ethanol enhanced fluid secretion and caused a transient increase of intracellular Ca^<2+>. On the contrary, propanol and butanol inhibited fluid secretion and lowered intracellular Ca^<2+>. This "cut-off effect" suggests alcohols act directly on some ion channels of pancreatic duct cells.