Alanine aminotransferase distribution

Some enzymes show relatively high activity in only one or a few tissues. The presence of increased levels of these enzymes in plasma thus reflects damage to the corresponding tissue. For example, the enzyme alanine aminotransferase ALT, see p. 248) is abundant in the liver. The appearance of elevated levels of ALTin plasma signals possible damage to hepatic tissue. Increases in plasma levels of enzymes with a wide tissue distribution provide a less specific indication of the site of cellular injury. This lack of tissue specificity limits the diagnostic value of many plasma enzymes. 

DeRosa, C., and Swiefc, R. W- (1975). Metabolic implications of the distribution of the alanine aminotransferase isoenzymes. /. Biol. Chem. 2S0, 7961-7967. 

The selection of which enzyme to measure in serum for diagnostic or prognostic purposes depends on a number of factors. An important factor is the distribution of enzymes among the various tissues, shown, for example, for aspartate aminotransferase, alanine aminotransferase, and creatine kinase in Figure 8-14. The main enzymes of established clinical value, together with their tissues of origin and their major clinical applications, are listed in Table 8-3 (see also Chapter 21). 

There are five enzymes that are commonly used in diagnosis of liver disease Aspartate aminotransferase (AST EC 2.6.1.1), alanine aminotransferase (ALT EC 2.6.1.2), alkaline phosphatase (ALP 3.1.3.1), and y-glutamyl transferase (GGT EC 2.3.2.2), are commonly used to detect liver injury, and lactate dehydrogenase (LD EC 1.1.1.27) is occasionaEy used. ALT and GGT are present in several tissues, but plasma activities primarily reflect liver injury. AST is found in liver, muscle (cardiac and skeletal), and to a liipited extent iti fed cells. LD has wide tissue distribution, and is thus relatively nonspecific. ALP is found in a number of tissues, but in normal individuals primarEy reflects bone and liver sources. Thus based on tissue distribution, ALT and GGT would seem to be the most specific markers for liver injury. 

Often there is no good clinical test available to determine the exact type of hepatic lesion, short of liver biopsy. There are certain patterns of enzyme elevation that have been identified and can be helpful (Table 38-3). ° The specificity of any serum enzyme depends on the distribution of that enzyme in the body. Alkaline phosphatase is found in the bile duct epithelium, bone, and intestinal and kidney cells. 5-Nucleotidase is more specific for hepatic disease than alkaline phosphatase, because most of the body s store of 5 -nucleotidase is in the liver. Glutamate dehydrogenase is a good indicator of centrolobular necrosis because it is found primarily in centrolobular mitochondria. Most hepatic cells have extremely high concentrations of transaminases. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) are commonly measured. Because of their high concentrations and easy liberation from the hepato-cyte cytoplasm, AST and ALT are very sensitive indicators of necrotic lesions within the liver. After an acute hepatic lesion is established, it may take weeks for these concentrations to return to normal. ... 

Several of the common enzyme measurements aimed at detecting hepatotoxicity are not specific to the liver, show a widespread tissue distribution, and are therefore affected by damage to extrahepatic tissue (e.g., alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase following injury to cardiac or skeletal muscles). The development of troponin assays has provided an alternative to enzyme measurements as indicators of cardiotoxicity, but not for myotoxicity here, the timing and the methods of sample collection are particularly critical for the detection of cardiac or muscle damage (see Chapter 7). 

The metabolic steps in gluconeogenesis occur in two intracellular compartments (Fig. 3.2) the cytosol and the mitochondrial matrix. The enzymes of the tricarboxylic acid cycle reside in the mitochondrial matrix, apart from succinate dehydrogenase which is present in the inner mitochondrial membrane, whereas most of the enzymes of the gluconeogenic pathway are present in the cytosol. Transaminases, such as alanine aminotransferase and aspartate aminotransferase, are present both in mitochondria and cytosol of the domestic fowl liver (Sarkar, 1977). One of the control enzymes in gluconeogenesis, PEPCK, has a different intracellular distribution in avian liver compared with mammalian liver (Table 3.3). PEPCK in both pigeon and domestic fowl liver is present almost exclusively (> 99%) in mitochondria (Soling et al.. 1973), whereas in most mammals that have been studied, it is present mainly in the cytosol, and only present, if at all, in smaller amounts in... 

See color insert.) Distribution of alanine aminotransferase (ALT) by time and treatment. Maximiun value for each subject over the course of the 24 weeks is displayed in the right panel. (From CTSpedia, http //www.ctspedia.org/do/view/CTSpedia/ClinLFTGraph007, accessed January 8, 2013. Contributed by Robert Gordon original plot cited in Amit, O. et al., Phamt. Stat, 7,20,2008.)... 

Unlike glycolysis, which occurs strictly in the cell cytosol, gluconeogen-esis involves a complex interaction between the mitochondrion and the cytosol. This interaction is necessitated by the irreversibility of the pyruvate kinase reaction, by the relative impermeability of the inner mitochondrial membrane to oxaloacetate, and by the specific mitochondrial location of pyruvate carboxylase. Compartmentation within the cell has led to the distribution of a number of enzymes (aspartate and alanine aminotransferases, and NAD -malate dehydrogenase) in both the mitochondria and the cytosol. In the classical situation represented by the rat, mouse, or hamster hepatocyte, the indirect "translocation" of oxaloacetate—the product of the pyruvate carboxylase reaction—into the cytosol is effected by the concerted action of these enzymes. Within the mitochondria oxaloacetate is converted either to malate or aspartate, or both. Following the exit of these metabolites from the mitochondria, oxaloacetate is regenerated by essentially similar reactions in the cytosol and is subsequently decarboxylated to P-enolpyruvate by P-enol-pyruvate carboxykinase. Thus the presence of a membrane barrier to oxaloacetate leads to the functioning of the malate-aspartate shuttle as an important element in gluconeogenesis. 

Waner, T. 1991. Population distribution profiles of the activities of blood alanine and aspartate aminotransferase in the normal F344 inbred rat by age and sex. Laboratory Animals 25 263-271. 

The synthesis of alanine in chloroplasts has been questioned due to the apparent lack of an appropriate aminotransferase in these oiganelles (Biek-mann and Feierabend, 1982). Contrasting conclusions can be drawn fi-om the results of other studies. For example, alanine synthesis from [2- ]pyruvate or [ C]bicarbonate has been demonstrated in purified spinach chloroplasts (Schulze-Siebert et ai, 1984). Since the rate of alanine synthesis from pyruvate was significantly enhanced upon rupture of the chloroplasts, the possibility that alanine synthesis was due to contaminants of the plastid preparations is diminished. These and other results noted above suggest that appropriate aminotransferases are widely distributed within plant cells. The availability of an... 

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