Mechanism of elevation of serum alkaline phosphatase activity in biliary obstruction: an experimental study.
ABSTRACT Bile duct ligation in rats increased alkaline phosphatase activity in serum and liver. In the serum, the activity reached a peak 24 h after bile duct ligation, earlier than in the liver. This finding indicates that the elevation of serum alkaline phosphatase activity is not due to simple overspill of this enzyme from the liver into the circulation. An electrophoretic study, employing polyacrylamide gel with Triton X-100, and a gel filtration study disclosed that 24 h after bile duct ligation the serum contained a high molecular weight form of alkaline phosphatase in addition to the hepatic and intestinal isoenzymes. The high molecular weight form was also found in bile, indicating that regurgitation of bile contributed to the increase in alkaline phosphatase activity in the serum. The absence of the high molecular weight alkaline phosphatase in the sera of rats with intrahepatic cholestasis induced by alpha-naphthylisothiocyanate suggests that, in this type of cholestasis, regurgitation of bile alkaline phosphatase does not play an important role in the elevation of serum alkaline phosphatase activity. These findings indicate that the high molecular weight alkaline phosphatase in serum is a useful diagnostic marker of biliary obstruction.
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ABSTRACT: Alkaline phosphatase (ALP) exists as several isoenzymes and many isoforms present in tissues and serum. The objective of this study was to separate tissue ALP forms in rats and humans and characterise their properties. The materials for the investigation were intestinal, bone, and liver tissue of rats and commercially available human preparations of tissue ALP. Two methods of separation were used: high-performance liquid chromatography (HPLC) and agarose gel electrophoresis. Using HPLC in the rat tissues, two ALP isoforms in the intestine, one in the bone, and three in the liver were identified. In humans three intestinal, two bone, and one liver isoform were resolved. Electrophoresis showed two ALP activity bands in rat intestine, one wide band in the bone, and three bands in the liver. ALP of human tissues was visualised as a single wide band, with a different mobility observed for each organ. In both species the presence of a form with properties characteristic of the bone isoform of the tissue-nonspecific isoenzyme was observed in the intestine. HPLC offers a higher resolution than electrophoresis with respect to tissue ALP fractions in rats and in humans, but electrophoresis visualises high-molecular-mass insoluble enzyme forms.Biochimie 03/2009; 91(3):445-52. · 3.14 Impact Factor
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ABSTRACT: Intrahepatic cholestasis involves impaired excretion of bile via the hepatobiliary system as a consequence of one or more lesions within the liver. In humans, intrahepatic cholestasis most often results as a side-effect of drug therapy and the clinical manifestation of this condition, jaundice, has been estimated to account for hospitalization in 2 to 5% of the cases for the general population and approaches as much as 20% in the elderly. With the aging of the population and the common occurrence of poly-drug therapy in geriatric patients, it is to be expected that jaundice due to drug-induced intrahepatic cholestasis will become even more prevalent, and accordingly the need to understand the basic mechanisms of this disease condition will become more urgent. The list of culprit agents implicated in the induction of intrahepatic cholestasis in humans is continually expanding. These include various steroid hormones, bile acids, drugs and other chemicals. Experimentally, a wide spectrum of agents has been shown to precipitate intrahepatic cholestasis. Over the years, a number of hypotheses on the biochemical and pathological mechanisms of intrahepatic cholestasis has emerged, including the following: impaired sinusoidal membrane function; interference with the distribution and binding of cytoplasmic endogenous carrier proteins; interference with mitochondrial energy supply; defects in the canalicular membrane including altered Na+/K+ -ATP-ase activity; impairment of microfilament and microtubule functions; interference with bile secretion involving bile acid dependent and independent fractions, and altered bile acid metabolism due to "hypoactive hypertrophic smooth endoplasmic reticulum". In partial agreement with the latter hypothesis, our studies indicated that impairment of the endoplasmic reticulum might represent one of the early stages in the development of intrahepatic cholestasis. Various experimental conditions that induce intrahepatic cholestasis to different degrees resulted in an interference of the synthesis of microsomal phospholipids and altered microsomal function. The conditions included the administration of various hepatotoxic compounds or steroids, pregnancy, delayed development of the endoplasmic reticulum in neonates, and dietary methyl donor or choline deficiency. This review reports the biochemical-pathological mechanisms postulated to be involved in the genesis of intrahepatic cholestasis with specific reference to experimental models of drug-induced intrahepatic cholestasis. The important practical implications of cholestasis are also briefly surveyed.Drug metabolism and drug interactions 02/1992; 10(1-2):1-161.
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ABSTRACT: Dipeptidyl peptidase IV is a cell surface ectopeptidase with widespread tissue distribution. Recently it was shown to display extracellular matrix-binding properties; therefore its role in cirrhosis is of interest. The aim of this study was to use monoclonal antibodies directed against the human CD26 antigen (which has been shown to be dipeptidyl peptidase IV) to study the distribution of this molecule in normal human and cirrhotic liver. Identical staining was obtained with the three monoclonal antibodies (TaI, 1F7 and TS145) and enzyme histochemistry. In normal liver (n = 11) intense staining of hepatic acinar zones 2 and 3 was present, but little staining was seen in zone I. Hepatocyte staining was confined to the bile canalicular domain. In cirrhotic livers (n = 23) obtained at transplantation, staining of regenerating nodules without a zonal pattern was present. In addition, we saw staining of the lymphoid cell infiltrate and proliferating bile ductules. In a minority of cirrhotic biopsy specimens (four) staining of the basolateral hepatocyte domain in regenerating nodules was seen. Biopsy specimens from hepatic allografts (n = 28) were used as disease controls. These samples all showed preferential staining of zones 2 and 3, similar to that in normal biopsy specimens. Eleven of these samples showed staining of the basolateral and bile canalicular domains. In conclusion, the normal acinar distribution of dipeptidyl peptidase IV (zones 2 and 3) is lost in cirrhotic nodules. Furthermore, the altered membrane distribution of this molecule in cirrhosis and allograft rejection may allow increased hepatocyte extracellular matrix interactions during organ remodeling.Hepatology 07/1992; 15(6):1048-53. · 11.19 Impact Factor