Toxicology of Glucosidase Inhibitors

Bomhard, E.

doi:10.1007/978-3-662-09127-2_20

Cited by 6 publications

(10 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Treatment with some drugs that modify glucose metabolism as their pharmacological action, with slight and asymptomatic increases in serum transaminase levels in humans (Bomhard, 1996). Toxicology -itors have also demonstrated transient increases in blood transaminase levels but no histopathological evidence of hepatotoxicity (Tolman, 2000;Bomhard, 1996), although some non-clinical toxicology studies have revealed that very high doses of statins caused hepatocellular necro-sis in rabbits (Kornbrust et al, 1989). These clinical and -toxicity.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2009

View full text Add to dashboard Cite

-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...

show abstract

Section: Introductionmentioning

confidence: 99%

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

et al. 2009

View full text Add to dashboard Cite

show abstract

“…In non-clinical toxicology studies, increased transaminase activity in the blood is also noted in animals (rats and dogs) (Bomhard, 1996). The elevations are generally slight and are not accompanied by any findings suggestive of hepatotoxicity, although slight single cell necrosis of the hepatocytes was observed in a small percentage of rats receiving high doses of voglibose for 5 weeks.…”

Section: α-Glucosidase Inhibitors (α-Gis)mentioning

confidence: 95%

“…The elevations are generally slight and are not accompanied by any findings suggestive of hepatotoxicity, although slight single cell necrosis of the hepatocytes was observed in a small percentage of rats receiving high doses of voglibose for 5 weeks. Interestingly, in dogs, only moderately increased AST activities occurred after treatment with emiglitate and miglitol (Bomhard, 1996). In the dog, as a carnivorous species, gluconeogenesis from amino acids is normally much higher than in the rat, which would explain why the dog was less responsive with regard to the induction of these enzymes.…”

Section: α-Glucosidase Inhibitors (α-Gis)mentioning

confidence: 98%

“…Treatment with some drugs that modify glucose metabolism as their pharmacological action, such as α-glucosidase inhibitors (α-GIs), is sometimes associated with slight and asymptomatic increases in serum transaminase levels in humans (Bomhard, 1996;Gentile et al, 1999). Toxicology studies on lipid-lowering drugs and α-GIs have also demonstrated transient increases in transaminase levels in the blood but no histopathological evidence of hepatotoxicity (Tolman, 2000;Bomhard, 1996), although some non-clinical toxicology studies have revealed that very high doses of statins caused hepatocellular necrosis in rabbits (Kornbrust et al, 1989). These clinical and non-clinical findings indicate that mild, reversible and asymptomatic transaminase elevations do not necessarily reflect hepatotoxicity.…”

Section: Drugs and Transaminase Elevationsmentioning

confidence: 99%

See 1 more Smart Citation

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

2020

View full text Add to dashboard Cite

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.

show abstract

“…Acarbose administered in the diet was associated with the development of a moderate incidence of RTT, including carcinomas, in male and female Sprague-Dawley rats. There was also a marked reduction, up to 50%, in body weight gain (Schlüter 1988; Bomhard 1996). These authors observed that simultaneous feeding of acarbose and glucose (the absorption of which is not prevented by acarbose), or administering acarbose by gavage after feed intake, negated any renal tumor effect.…”

Section: Exaggerated Pharmacologic Response (Involving Carbohydrate Mmentioning

confidence: 99%

Mechanisms of Rodent Renal Carcinogenesis Revisited

Hard¹

2018

Toxicol Pathol

View full text Add to dashboard Cite

The important renal tumors that can be induced by exposure of rats to chemical carcinogens are renal tubule tumors (RTTs) derived from tubule epithelium; renal pelvic carcinoma derived from the urothelial lining of the pelvis; renal mesenchymal tumors (RMTs) derived from the interstitial connective tissue; and nephroblastoma derived from the metanephric primordia. However, almost all of our knowledge concerning mechanisms of renal carcinogenesis in the rodent pertains to the adenomas and carcinomas originating from renal tubule epithelium. Currently, nine mechanistic pathways can be identified in either the rat or mouse following chemical exposure. These include direct DNA reactivity, indirect DNA reactivity through free radical formation, multiphase bioactivation involving glutathione conjugation, mitotic disruption, sustained cell proliferation from direct cytotoxicity, sustained cell proliferation by disruption of a physiologic process (alpha 2u-globulin nephropathy), exaggerated pharmacologic response, species-dominant metabolic pathway, and chemical exacerbation of chronic progressive nephropathy. Spontaneous occurrence of RTTs in the rat will be included since one example is a confounder for interpreting kidney tumor results in chemical carcinogenicity studies in rats.

show abstract

Toxicology of Glucosidase Inhibitors

Cited by 6 publications

References 29 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

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

Mechanisms of Rodent Renal Carcinogenesis Revisited

Contact Info

Product

Resources

About