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Clinical and pathophysiologic studies of increased alkaline phosphatase isoenzymes in the liver and serum of dogs

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Title: Clinical and pathophysiologic studies of increased alkaline phosphatase isoenzymes in the liver and serum of dogs
Author(s): Solter, Philip Frederick
Doctoral Committee Chair(s): Hoffmann, Walter E.
Department / Program: Pathobiology
Discipline: Pathobiology
Degree Granting Institution: University of Illinois at Urbana-Champaign
Degree: Ph.D.
Genre: Dissertation
Subject(s): Biology, Veterinary Science
Abstract: The clinical and pathophysiologic conditions necessary for liver alkaline phosphatase isoenzymes to increase in canine blood were examined. It was first shown by a clinical study that increased serum activity of the corticosteroid-induced isoenzyme of alkaline phosphatase (CALP), which is unique to dogs, occurs in many different disease states. Further studies were performed to determine the possible underlying mechanisms responsible for this increase. Using gas chromatography/mass spectrometry it was shown that both CALP and liver alkaline phosphatase (LALP) purified from canine serum, contain myo-inositol residues in near equimolar amounts to the respective alkaline phosphatase monomer. This is consistent with release of alkaline phosphatase from hepatocyte membranes by endogenous glycosyl-phosphatidylinositol phospholipase D (GPI-PLD). Release of CALP and LALP into serum by GPI-PLD activity was supported by Western blot analyses using anti-cross reacting determinant antibodies and non-denaturing polyacrylamide gel electrophoresis.Results of hepatic nuclear scintigraphy and transmission electron microscopy suggested that cholestasis is minimal in dogs with experimentally-induced glucocorticoid hepatopathy. Paired serum samples from 11 clinically diseased dogs showed that the ratio of CALP to LALP activity in bile was substantially different from the ratio in serum. Histochemical stains revealed alkaline phosphatase activity on the sinusoidal surfaces of hepatocytes in dogs with glucocorticoid hepatopathy. From these findings, it was concluded that serum alkaline phosphatase activity likely originates from the sinusoidal surfaces of hepatocytes rather than from bile regurgitation.Further experiments performed using isolated canine hepatocytes and hepatocyte membrane fragments revealed that membrane-bound alkaline phosphatase isoenzymes are highly resistant to GPI-PLD activity unless first treated with detergents, such as bile acids. However, hepatic bile acid concentrations in dogs with experimentally-induced glucocorticoid hepatopathy were not increased over values in healthy controls, in spite of significant increases in serum alkaline phosphatase activity. By inducing acute gall bladder emptying with intravenous infusions of cholecystokinin octapeptide (CCK-OP), a significant increase in alkaline phosphatase activity could be induced in dogs with glucocorticoid hepatopathy. This suggested that the release of alkaline phosphatase from hepatic membranes by GPI-PLD may occur secondary to the enterohepatic circulation of bile acids through the liver. However, a direct effect of CCK-OP on alkaline phosphatase release could not be ruled out.
Issue Date: 1994
Type: Text
Language: English
URI: http://hdl.handle.net/2142/20188
Rights Information: Copyright 1994 Solter, Philip Frederick
Date Available in IDEALS: 2011-05-07
Identifier in Online Catalog: AAI9512555
OCLC Identifier: (UMI)AAI9512555
 

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