Inhibition of Partially Purified Sorbitol Dehydrogenase Activity From Sera of Patients With Type I Diabetes (original) (raw)
Related papers
Glycation and inactivation of sorbitol dehydrogenase in normal and diabetic rats
The Biochemical journal, 1996
Sorbitol dehydrogenase (SDH) is involved in the polyol pathway, which plays an important role in the pathogenesis of diabetic complications. We have measured the tissue distributions of SDH mRNA, both the immunoreactive enzyme levels and the enzyme activity. SDH mRNA was especially abundant in liver, kidney and testis. Both the activity and enzyme content are high in liver and kidney but not in testis. The discrepancy between mRNA and immunoreactive enzyme levels and the activity of SDH observed in testis was also seen in livers of streptozotocin-induced diabetic rats. SDH was found to exist in both glycated and non-glycated forms, with larger amounts of the glycated protein in the diabetic liver. Moreover, after incubation of purified enzyme with glucose or fructose, its activity was markedly decreased. These results indicate that glycation causes a decrease in SDH activity in liver under diabetic conditions. The same post-transcriptional event might occur to decrease the activity ...
Study of Renal Sorbitoldehydrogenase in Experimental Diabetic Nephropathy
Southern Brazilian Journal of Chemistry, 1998
The link between the po/yo/ pathway and the occular complications of diabetes mellitus is explained by the excessive storage of sorbitol and the release of osmotic stress. The renal complications could also be explained by the osmotic hypothesis, but the po/yo/ pathway activity is reduced in this case. The study of sorbitoldehydrogenase (SDH) activity, one of the enzymes involved in the catabolism of glucose by this pathway in renal and hepatic homogenates from diabetic animals shows a constant increase of the hepatic enzyme activity compared to that at the renal level. The different variation of the renal SDH activity can be explained by the effect of hyperglycemia on the active form of the enzyme and its inactivation by nonenzymatic glycosylation.
Journal of Medicinal Chemistry, 2002
We report here a novel sorbitol dehydrogenase inhibitor, 16, that shows very high oral potency (50 µg/kg) in normalizing elevated fructose levels in the sciatic nerve of chronically diabetic rats and sustained duration of action (>24 h). Furthermore, 16 shows attractive pharmaceutical properties, including good solubility in simulated human gastric fluid, excellent Caco-2 Papp, moderate lipophilicity, and metabolic stability for achieving good oral absorption and long duration of action. a Chronic test, b Side-by-side comparison, c Not determined, d 56% at 0.05 mpk. e 81% at 1 mpk. f 65% at 1 mpk.
Experimental Neurology, 2005
We have developed an animal model of diabetic sympathetic autonomic neuropathy which is characterized by neuroaxonal dystrophy (NAD), an ultrastructurally distinctive axonopathy, in chronic streptozotocin (STZ)-diabetic rats. Diabetes-induced alterations in the sorbitol pathway occur in sympathetic ganglia and therapeutic agents which inhibit aldose reductase or sorbitol dehydrogenase improve or exacerbate, respectively, diabetes-induced NAD. The sorbitol dehydrogenase inhibitor SDI-711 (CP-470711, Pfizer) is approximately 50-fold more potent than the structurally related compound SDI-158 (CP 166,572) used in our earlier studies. Treatment with SDI-711 (5 mg/kg/day) for 3 months increased ganglionic sorbitol (26-40 fold) and decreased fructose content (20-75%) in control and diabetic rats compared to untreated animals. SDI-711 treatment of diabetic rats produced a 2.5-and 4-5-fold increase in NAD in the SMG and ileal mesenteric nerves, respectively, in comparison to untreated diabetics. Although SDI-711 treatment of non-diabetic control rat ganglia increased ganglionic sorbitol 40-fold (a value 8-fold higher than untreated diabetics), the frequency of NAD remained at control levels. Levels of ganglionic sorbitol pathway intermediates in STZ-treated rats (a model of type 1 diabetes) and Zucker Diabetic Fatty rats (ZDF, a genetic model of type 2 diabetes) were comparable, although STZ-diabetic rats develop NAD and ZDF-diabetic rats do not. SDI failed to increase diabetes-related ganglionic NGF above levels seen in untreated diabetics. Initiation of Sorbinil treatment for the last 4 months of a 9 month course of diabetes, substantially reversed the frequency of established NAD in the diabetic rat SMG without affecting the metabolic severity of diabetes. These findings indicate that sorbitol pathway-linked metabolic alterations play an important role in the development of NAD, but sorbitol pathway activity, not absolute levels of sorbitol or fructose per se, may be most critical to its pathogenesis. D 2004 Elsevier Inc. All rights reserved.
Evaluation of Sorbitol Dehydrogenase and Some Biochemical Parameters in Patients with Hepatitis
Kirkuk University Journal-Scientific Studies, 2019
This research was concerned with a study of the relationship between sorbitol dehydrogenase and hepatitis disease. Blood samples have been drawn from (35) patients with hepatitis and (28) blood samples of healthy as control group ages ranges from (40-65) years. Patients were collected from Al-Salam Hospital in Mosul City under the supervision of specialists Live in Mosul city. Sorbitol dehydrogenase, total serum bilirubin, protein, albumin, globulin and alanine aminotransferase sGPT were measured in blood of these patients. The results showed a significant increase in sorbitol dehydrogenase, sGPT, bilirubin, total serum protein, albumin and globulin levels compared with the control group. There was also study of the relationship between (SDH) activity and the studied parameters in patient group and finding that there are liner correlation coefficient. the results indicated that, there was a positive significant correlation between the activity of enzyme and each of the total protein, albumin, globulin, sGPT, and bilirubin and negative significant corolation between SDH and globulin.
Experimental Eye Research, 1998
Several recent studies with the sorbitol dehydrogenase inhibitors 4- [4-(N,N-dimethylsulfamoyl)piperazino]-2-methylpyrimidine, SDH-1, and its active metabolite 4-[4-(N,N-dimethylsulfamoyl)piperazino]-2-hydroxymethylpyrimidine, SDH-2, suggest that inhibition of sorbitol dehydrogenase may be beneficial in delaying the onset of diabetic complications due to their ability to ameliorate redox changes associated with polyol metabolism. To compare the relative importance of sorbitol dehydrogenase versus aldose reductase inhibition on sugar cataract formation, cataract formation was monitored in 50 % galactose-fed and diabetic rats treated with\without the sorbitol dehydrogenase inhibitors SDH-1 or SDH-2 or the aldose reductase inhibitors AL 1576 or Ponalrestat. For these studies, diabetes was induced in young 50 g rats with streptozotocin while galactosemia was produced by feeding a diet containing 50 % galactose. Inhibitors were administered in the diet with the diet containing 0n06 % (w\w) of the sorbitol dehydrogenase inhibitors or Ponalrestat, and 0n0125 % (w\w) of AL 1576. Cataract formation was monitored by hand-held slit lamp and polyol levels were measured by gas chromatography.
… of Neuropathology & …, 2001
We have developed an animal model of diabetic autonomic neuropathy that is characterized by neuroaxonal dystrophy (NAD) involving ileal mesenteric nerves and prevertebral sympathetic superior mesenteric ganglia (SMG) in chronic streptozotocin (STZ)-diabetic rats. Studies with the sorbitol dehydrogenase inhibitor SDI-158, which interrupts the conversion of sorbitol to fructose (and reactions dependent on the second step of the sorbitol pathway), have shown a dramatically increased frequency of NAD in ileal mesenteric nerves and SMG of SDI-treated versus untreated diabetics. Although lesions developed prematurely and in greater numbers in SDI-treated diabetics, their distinctive ultrastructural appearance was identical to that previously reported in long-term untreated diabetics. An SDI effect was first demonstrated in the SMG of rats that were diabetic for as little as 5 wk and was maintained for at least 7.5 months. As in untreated diabetic rats, rats treated with SDI i) showed invo...
X-Ray Crystallographic and Kinetic Studies of Human Sorbitol Dehydrogenase
Structure, 2003
A leading metabolic approach to control the detrimental effects of excess flux of glucose in diabetic tissues Groton, Connecticut 06340 4 Lawrence Berkeley Laboratory has been to inhibit aldose reductase (AR), the first enzyme of the polyol pathway (Figure 1A). Aldose reduc-1 Cyclotron Road, MS 4-230 Berkeley, California 94720 tase inhibitors have shown promising preclinical results in animal models of diabetic complications (Sarges and Oates, 1993) and have recently been reported to improve neuropathy and nephropathy surrogate endpoints in Summary early clinical trials (Greene et al., 1999; Hotta et al., 2001; Iso et al., 2001). A closely related concept (Williamson Sorbitol dehydrogenase (hSDH) and aldose reductase form the polyol pathway that interconverts glucose et al., 1993; recently reviewed in Tilton, 2002; Oates, 2002) emphasizes the importance of the increase in the and fructose. Redox changes from overproduction of the coenzyme NADH by SDH may play a role in diabe-cytoplasmic free NADH/NAD ϩ ratio that results from excessive oxidation of sorbitol to fructose by SDH, creat-tes-induced dysfunction in sensitive tissues, making SDH a therapeutic target for diabetic complications. ing a "pseudo-hypoxic" state that contributes to glucose-linked oxidative stress (Williamson et al., 1993; We have purified and determined the crystal structures of human SDH alone, SDH with NAD ؉ , and SDH with Tilton, 2002) and is therefore a central determinant of vascular dysfunction and eventual pathology in diabetic NADH and an inhibitor that is competitive with fructose. hSDH is a tetramer of identical, catalytically ac-tissues (Rosen et al., 2001). Specific inhibitors of SDH are needed to study the role of excess flux through SDH tive subunits. In the apo and NAD ؉ complex, the catalytic zinc is coordinated by His69, Cys44, Glu70, and in the development of diabetic complications. Prototype sorbitol dehydrogenase inhibitor (SDI) CP-a water molecule. The inhibitor coordinates the zinc through an oxygen and a nitrogen atom with the con-166,572 (SDI-158; Figure 1B) was identified in 1994 (Geissen et al., 1994) and provided the starting point comitant dissociation of Glu70. The inhibitor forms hydrophobic interactions to NADH and likely sterically from which more potent SDIs were synthesized (Mylari et al., 2001, 2002; Chu-Moyer et al., 2002). Although it occludes substrate binding. The structure of the inhibitor complex provides a framework for developing has been proposed that the compound inhibits enzyme activity by directly chelating the catalytic zinc (Mylari more potent inhibitors of hSDH. et al., 2001; Lindstad and McKinley-McKee, 1997), a definitive proof, such as a crystal structure, has not been Introduction available. Recently, two X-ray crystal structures have contributed to our knowledge of the SDH enzymes. The Diabetes mellitus afflicts approximately 151 million peo-3.0 Å resolution structure of rat sorbitol dehydrogenase ple worldwide, with an estimated increase to 221 million has been determined (Johansson et al., 2001), as has by 2010 (Zimmet et al., 2001). Diabetic individuals often a high-resolution structure of the silverleaf whitefly suffer debilitating long-term complications such as NADP(H)-dependent ketose reductase (Banfield et al., 2001), which preferentially catalyzes the reduction of *Correspondence: virginiar@thiospharm.com 5 Current address: Pfizer Global Research and Development, La Jolla fructose to sorbitol. Crystals of human SDH have also Laboratories, 3665 General Atomics Court, San Diego, California 92121. been reported (Darmanin et al., 2003). 6 Current address: Department of Biochemistry and Molecular Biol-Here, we present the first X-ray crystal structures of ogy, Michigan State University, East Lansing, Michigan 48824. human sorbitol dehydrogenase (hSDH, E.C. 1.1.1.14), 7 Current address: Pfizer Discovery Technology Center, 620 Memoas well as hSDH plus its required cofactor, NAD ϩ , and rial Drive, Cambridge, Massachusetts 02139. a ternary complex of hSDH, NADH, and a reversible 8 Current address: active site inhibitor, CP-166,572. These X-ray structures