Diagnostic application of mitochondrial enzymes and isoenzymes

Schmidt, F. W.; Schmidt, E.

doi:10.1016/0009-8981(89)90215-5

Cited by 6 publications

(3 citation statements)

References 28 publications

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“…A good correlation was obtained between these two parameters both for ALT (r = 0.839, p < 0.01) and AST (r = 0.702, p < 0.01). The basal levels of transaminases in the blood are considered to be explained by the release of hepatocellular enzyme proteins into the circulation during normal cell turnover (Schmidt et al, 1989) and blood transaminase levels increase up to 10-100 fold when marked hepatocyte cell lysis occurred as the results of DILI. The results of the correlation analyses indicate that the slight increases in plasma transaminase activities release of increased hepatocellular enzyme proteins into the circulation during normal cell turnover.…”

Section: Discussionmentioning

confidence: 99%

Effects of fenofibrate on plasma and hepatic transaminase activities and hepatic transaminase gene expression in rats

et al. 2009

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-Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels are widely used as sensitive markers of possible tissue damage, particularly liver toxicity. Lipid-lowering that the phenomenon is related to drug-induced liver injury (DILI). Some in vitro studies have indicatleakage from the hepatocytes associated with cell lysis. In this study, male F344/DuCrlCrlj (Fischer) rats -macological effects, blood and hepatic transaminase activities and the gene expression of the transami--in parallel with increases in hepatic transaminase activities associated with increases in the transaminase genes in the liver and were not considered to be a consequence of hepatotoxicity from the drug. The mod--brate. The evidence obtained in our study underlines the importance of gene regulation as a possible alternative mechanism for increased blood transaminase activities.Correspondence: Akio Kobayashi (E-mail: akio.kobayashi@jt.com) Original ArticleThe Journal of Toxicological Sciences (J. Toxicol. Sci.) Vol.34, No.4, 377-387, 2009 Vol. 34 No. 4 377 sis in rabbits (Kornbrust et al., 1989). These clinical and -toxicity. Possible mechanisms for the transaminase elevation include increased transaminase synthesis, decreased transaminase clearance and transaminase leakage from hepatocytes whose membranes may have been altered by changes in their lipid content. Transaminases, both ALT and AST, are some of the key enzymes involved in amino acid/glucose metabolism pathways and play an important role in gluconeogenesis in the liver and kidney (DeRosa and Swick, 1975). Taking the functions of transaminases into account, transaminase synthesis must be altered as well as for other enzymes involved in the amino acid/ glucose metabolism pathways if hormonal or nutritional fluctuation, which leads to acceleration or deceleration of gluconeogenesis, occurs. In fact, the expression of the rat cytosolic AST gene in the hepatoma cell line Fao is modified by glucocorticoids, insulin and cAMP (Aggerbeck et al., 1993;Barouki et al., 1989) and by a protein-rich diet or during prolonged fasting (Horio et al., 1988). Further, ALT and AST levels in the serum and organs are increased by these hormonal and nutrition- et al., 1966;Ramesh and Pugalendi, 2005;Rosen et al., 1959; Hoffman et al., 1989). Elevation of transaminase activities in the serum or organs associated with hormonal or nutritional modifications are slight in mag--tive of tissue damage including hepatocellular necrosis. These nutritional or hormonal aspects for the elevation of transaminase activities have led some researchers to in vitro studies for the investigations of the relationship between transaminase activities and their gene expression in human and animal hepatocytes treated with drugs which modify lipid metabolism as their pharmacological action. Edgar et al increased ALT and AST activities in human HepG2 cells as well as both mRNA levels. Another in vitro study conducted by Tomkiewicz et al -brate increased the expression of the cytosolic AST gene i...

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Section: Discussionmentioning

confidence: 99%

Effects of fenofibrate on plasma and hepatic transaminase activities and hepatic transaminase gene expression in rats

et al. 2009

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“…The physiological role of these enzymes in the extramitochondrial blood coagulation process is not at present known. The leakage of mitochondrial enzymes in different pathogenic and abnormal physiological states [31,32] may indicate the possibility that in some abnormal physiological conditions these enzymes leach out of the mitochondria into the blood and participate in blood coagulation.…”

Section: Discussionmentioning

confidence: 99%

Characterization of a membrane protease from rat submaxillary-gland mitochondria that possess thrombin-like activity

Bharadwaj

Hati

1996

Biochemical Journal

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A membrane protease possessing thrombin-like activity was purified to homogeneity from mitochondria of rat submaxillary gland. The molecular mass of the enzyme was determined to be 45 kDa by SDS/PAGE under reducing conditions and by gel filtration on a Sephadex G-100 column. The enzyme is a glycoprotein and has an isoelectric point of 3.25. Maximum activity was observed at pH 10.5. Inhibition by di-isopropyl fluorophosphate, benzamidine, aprotinin and antipain suggested the enzyme to be a serine protease. Other inhibitors such as EDTA, soya-bean trypsin inhibitor, lima-bean trypsin inhibitor, TosLysCH2Cl and chymostatin did not alter the activity. The enzyme showed affinity towards different synthetic substrates (p-nitroanilide derivatives) containing arginine at the P1 position. Kinetic studies revealed that Kcat./Km was highest with the substrate N-Bz-Phe-Val-Arg-p-nitroanilide. The enzyme exhibits significant plasma-coagulating activity. The coagulation initiated by the enzyme was not altered by concanavalin A, indicating that the carbohydrate moiety of the enzyme is not essential for this reaction. Further, this enzyme can catalyse the formation of fibrin clots from purified fibrinogen, which describes its thrombin-like activity. However, an antibody raised against the purified enzyme inhibited the plasma-clotting as well as fibrinogen-clotting activity of the enzyme. Fibrinogen coagulation by the enzyme was blocked in the presence of aprotinin, a protease inhibitor. Release of fibrinopeptides A and B from bovine fibrinogen by the enzyme has been shown by HPLC analysis. Our studies reveal that the enzyme reported here differs from trypsin, chymotrypsin and other mitochondrial proteases reported so far.

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“…The basal levels of transaminases in the blood can be explained by the release of cellular enzyme proteins into the circulation during normal cell turnover (Schmidt and Schmidt, 1989). Although the main source of the enzyme is considered to be the liver (Schmidt and Schmidt, 1989), other sources should be taken into consideration based on the enzyme activity and the size of the organ/tissues when transaminase activity is increased in the blood. In other words, transaminase activity in the blood is considered to be the sum of the activities of transaminase released from different transaminase-rich tissues into the circulation during normal cell turnover.…”

Section: Distribution Of Alt and Ast In Organs And Tissuesmentioning

confidence: 99%

Specificity of transaminase activities in the prediction of drug-induced hepatotoxicity

2020

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The activities of the transaminases (aminotransferases) alanine aminotransferase and aspartate aminotransferase in the blood (serum or plasma) are widely used as sensitive markers of possible tissue damage and, in particular for liver toxicity. On the other hand, an increase in transaminase activities is not always accompanied by findings suggestive of hepatotoxicity. Transaminases are some of the key enzymes in the gluconeogenesis and glycolysis pathways and exist in many organs and tissues which have high activities of the gluconeogenesis and glycolysis. The activities of transaminases are altered not only in the liver but also in other organs by modification of gluconeogenesis by nutritional or hormonal factors and this phenomenon leads to alteration of transaminase activity in the blood. Drugs, which are considered to directly or secondarily modify gluconeogenesis through lowering blood glucose levels or activating lipid metabolism, such as α-glucosidase inhibitors and fibrates, slightly increase transaminase activities in the blood but there is little evidence that the phenomenon is related to drug-induced liver injury (DILI). This type of elevations can be called pharmacology-related elevation. The pharmacology-related elevation of transaminase activities sometimes makes it difficult to assess precisely the potential hepatotoxicity of new investigational drugs. Considering the characteristic of transaminases, concomitant use of new biomarkers more specific to hepatic injury is needed in the assessment of DILI both in non-clinical and clinical studies. In this review, we will discuss the specificity of transaminases to DILI and future perspectives for transaminases in the estimation of risk of DILI.

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Diagnostic application of mitochondrial enzymes and isoenzymes

Cited by 6 publications

References 28 publications

Effects of fenofibrate on plasma and hepatic transaminase activities and hepatic transaminase gene expression in rats

Effects of fenofibrate on plasma and hepatic transaminase activities and hepatic transaminase gene expression in rats

Characterization of a membrane protease from rat submaxillary-gland mitochondria that possess thrombin-like activity

Specificity of transaminase activities in the prediction of drug-induced hepatotoxicity

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