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PubMed1992

The kinetic mechanism of sheep liver sorbitol dehydrogenase.

The relations between the kinetic parameters for both sorbitol oxidation and fructose reduction by sheep liver sorbitol dehydrogenase show that a Theorell-Chance compulsory order mechanism operates from pH 7.4 to 9.9. This is supported by many parallels with the kinetics of horse liver alcohol dehydrogenase, which operates by this classical mechanism. An isotope-exchange study using D-(2H8)sorbitol confirmed the existence of ternary complexes and that, under maximum velocity conditions, their interconversion is not rate-determining. Substrate inhibition at high concentrations of D-sorbitol or D-fructose confirmed rate-determining enzyme--coenzyme product dissociation, slowed by the existence of more stable abortive ternary enzyme-coenzyme product complexes with substrate. The effect of the inhibitor/activator 2,2,2-tribromoethanol showed the existence of enzyme-NAD-CBr3CH2OH complexes inhibiting the first phase of reaction and enzyme-NADH-CBr3CH2OH complexes dissociating more rapidly than the usual rate-determining enzyme-NADH coenzyme product dissociation in the final phase. Inhibition studies with dithiothreitol also confirmed an ordered binding of coenzymes and second substrates to sorbitol dehydrogenase. Neither D-sorbitol nor D-fructose had any effect on enzyme inactivation by the affinity labelling reagent DL-2-bromo-3-(5-imidazolyl)propionic acid, thus giving no evidence for their existence as binary enzyme-substrate complexes. Several alternative polyol substrates for sorbitol dehydrogenase gave the same maximum velocity as sorbitol. This indicated a common rate-limiting binary enzyme-NADH product dissociation and a similarity of mechanism. An enzyme assay for pH 7.0 and 9.9 is given which enables the concentration of sorbitol dehydrogenase to be determined from initial rate measurements of enzyme activity.

Animals↗
PubMed1990

Effect of fructose supplementation on sorbitol accumulation and myo-inositol metabolism in cultured neuroblastoma cells exposed to increased glucose concentrations.

Aldose reductase activity is increased in neuroblastoma cells grown in media containing 30 mM fructose and/or 30 mM glucose. Neuroblastoma cells cultured in media supplemented with increased concentrations of glucose and fructose amass greater amounts of sorbitol than do cells exposed to media containing only high glucose concentrations. The increase in sorbitol content is dependent on the fructose and glucose concentration in the media. The increase in sorbitol content caused by exposing neuroblastoma cells to media containing 30 mM glucose/30 mM fructose is due to a protein synthesis sensitive mechanism and not to an alteration in the redox state. The addition of sorbinil to media containing 30 mM glucose blocks the increase in sorbitol content. In contrast, sorbinil treatment of media containing 30 mM glucose/30 mM fructose does not totally block the increase in sorbitol levels. myo-Inositol accumulation and incorporation into inositol phospholipids and intracellular myo-inositol content are decreased in cells chronically exposed to media containing 30 mM glucose or 30 mM glucose/30 mM fructose compared to cells cultured in unsupplemented media or media containing 30 mM fructose. However, maximal depletion of myo-inositol accumulation and intracellular content occurs earlier in cells exposed to media containing 30 mM glucose/30 mM fructose than in cells exposed to media supplemented with 30 mM glucose. Sorbinil treatment of media containing 30 mM glucose/30 mM fructose maintains cellular myo-inositol accumulation and incorporation into phospholipids at near normal levels. myo-Inositol content in neuroblastoma cells chronically exposed to media containing 30 mM glucose or 30 mM glucose/30 mM fructose recovers within 72 h when the cells are transferred to unsupplemented media or media containing 30 mM fructose. In contrast, the sorbitol content of cells previously exposed to media containing 30 mM glucose or 30 mM glucose/30 mM fructose then transferred into media containing 30 mM fructose remains elevated compared to the sorbitol content of cells transferred into unsupplemented media. These data suggest that fructose may be activating or increasing sorbinil-resistant aldose reductase activity as well as partially blocking sorbitol dehydrogenase activity. The presence of increased concentrations of fructose in combination with increased glucose levels may enhance alterations in cell metabolism and properties due to increased sorbitol levels.

Aldehyde Reductase↗
PubMed1972

Reversal of the mannitol-sorbitol diauxie in Escherichia coli.

In Escherichia coli K-12 the proteins involved in the dissimilation of mannitol and sorbitol are specified by two separate gene clusters. The mannitol cluster appears to consist of a regulatory gene mtlC, a gene mtlA coding an enzyme II complex of the phosphoenolpyruvate phosphotransferase system, and a gene mtlD coding a mannitol-1-phosphate dehydrogenase. Three corresponding genes, sblC, sblA, and sblD, exist for the sorbitol pathway. In both pathways the hexitol captured from the medium and delivered into the cytoplasm as a phosphorylated compound is dehydrogenated to fructose-6-phosphate. The enzyme II complex for sorbitol is able to catalyze the phosphorylation also of mannitol if this substrate is present at high concentrations. Consequently mtlA(-) mutants lacking the enzyme II complex for mannitol can grow on mannitol either if the sorbitol phosphorylating system is preinduced by sorbitol or if mtlA is suppressed by a mutation of sblC to constitutivity. In wild-type cells, the induction of the enzymes in the mannitol pathway and dissimilation of the substrate are not prevented by glucose. The sorbitol system, however, is sensitive to glucose and to mannitol as well. In the suppressed strains (mtlA(-), sblC(c)) in which mannitol is utilized through the sorbitol enzyme, glucose becomes effective in restraining the consumption of mannitol, causing a definite diauxie. Moreover, in a mixture of mannitol and sorbitol, the latter is utilized preferentially. This reversal of normal diauxic pattern is consequent to the fact that the enzyme II complex for sorbitol has relatively poor affinity for mannitol.

Alcohol Oxidoreductases↗
PubMed1988

Sorbitol malabsorption in normal volunteers and in patients with coeliac disease.

Sorbitol is a hexahydroxy alcohol used as a sugar substitute in many dietetic foods and as a drug vehicle. Previous studies have suggested that sorbitol ingestion may be an additional cause of non-specific gastrointestinal distress. We evaluated sorbitol malabsorption in 30 healthy volunteers, seven patients with untreated coeliac disease and nine patients with coeliac disease on a gluten free diet, using a four hour H2 breath test. After ingestion of test solutions containing sorbitol 10 and 20 g and of four sweets (6.8 g sorbitol), 90%, 100%, and 62% of healthy volunteers, respectively had significantly raised H2 excretion, indicating malabsorption of sorbitol. Of all healthy subjects tested, 45% after 10 g, 100% after 20 g, and 50% after four sweets complained of symptoms of carbohydrate intolerance during the eight hours after sorbitol. After a 5 g dose given at concentrations of 2%, 4%, 8%, 16%, malabsorption was shown in 10%, 12%, 22%, and 43% of the healthy volunteers. Symptoms of intolerance at 5 g were experienced only at concentrations of 8% and 16%. Unlike healthy volunteers and coeliac patients on a gluten free diet, 100% of untreated coeliacs malabsorbed a 2% solution of 5 g sorbitol. These results show that malabsorption and intolerance of sorbitol may result from ingestion of doses and/or concentrations usually found in many foods and drugs; they underline the need to consider this as a possible and hitherto underestimated cause of gastrointestinal symptoms.

Adult↗
PubMed2001

Pharmacological properties of fidarestat, a potent aldose reductase inhibitor, clarified by using sorbitol in human and rat erythrocytes.

We examined the effect of fidarestat on the increase in sorbitol content in erythrocytes from healthy volunteers in vitro. Fidarestat inhibited the increase with an IC50 value of 18 nmol/l. A subsequent experiment showed that fidarestat had a similar inhibitory effect on the increase in sorbitol content in erythrocytes from diabetic patients. On the other hand, epalrestat, the only aldose reductase inhibitor used clinically, inhibited increase in sorbitol content at a concentration over 500-fold higher than fidarestat. Although the IC50 value of fidarestat was not affected by fasting plasma glucose, HbA1C, age, aldose reductase content or gender, there was a significant positive relationship between the IC50 value of epalrestat and fasting plasma glucose. In addition, in fidarestat (0.25-2 mg/kg)-treated diabetic rats, the inhibitory rate for erythrocyte sorbitol accumulation was well correlated with that for nerve sorbitol accumulation, which indicates that erythrocyte sorbitol is available for assessing the state of sorbitol pathway flux in target tissue after fidarestat administration. These results suggest that fidarestat potently inhibits the increase in sorbitol pathway flux in diabetic patients independent of various factors and that erythrocyte sorbitol is useful for its estimation.

Age Factors↗
PubMed1975

Antiketogenic action of fructose, glyceraldehyde, and sorbitol in the rat in vivo.

The purpose of this study was to compare the metabolism and antiketogenic properties of fructose, glyceraldehyde, and sorbitol. Fructose, glyceraldehyde, and sorbitol were readily metabolized and exhibited an antiketogenic effect in both blood and liver when injected intramuscularly to starved (forty-eight hours) rats. Sorbitol had the most pronounced antiketogenic effect and produced an 80 to 90 per cent decrease in the blood ketone bodies sixty minutes after administration. Fructose and glyceraldehyde were equally effective and produced about a 60 to 70 per cent decrease in ketone bodies. Fructose, glyceraldehyde, and sorbitol caused a significant decrease in the concentration of hepatic ketone bodies. In liver, sorbitol was found to be most effective in its antiketogenic action. The concentration of plasma free fatty acids remained unchanged after injection of all three antiketogenic substrates. Fructose, glyceraldehyde, or sorbitol caused increased blood lactate and pyruvate concentrations, and fructose was the most effective of the three substrates. Fructose administration resulted in a significant decrease in hepatic lactate/pyruvate and beta-OH-butyrate/acetoacetate concentration ratios, whereas sorbitol caused an increase in the concentration ratio of these two substrat pairs. Decreases in blood and liver ketone body levels were associated with lowering of liver acetyl-CoA concentration . However, the decrease in hepatic acetyl-CoA produced upon the administration of antiketogenic substrates was not pronounced. Sorbitol administration resulted in the most pronounced increase in hepatic alpha-glycerophosphate concentration. Fructose or glyceraldehyde also caused an increase in alpha-glycerophosphate content. Administration of each of the three antiketogenic substrates produced an increase in hepatic dihydroxyacetone phosphate concentration. All three antiketogenic compounds increased liver glycogen and blood glucose concentrations. No significant changes were observed in hepatic ATP, ADP, or AMP concentrations sixty minutes after the injections of any of the antiketogenic substrates. Although decreased liver acetyl-CoA levels were associated with the antiketogenic effects of the compounds tested, the increased liver alpha-glycerophosphate content best explains the differences between fructose or glyceraldehyde and sorbitol.

Acetyl Coenzyme A↗
PubMed1995

Inhibition of sorbitol dehydrogenase. Effects on vascular and neural dysfunction in streptozocin-induced diabetic rats.

These experiments were undertaken to assess the role of sorbitol dehydrogenase in mediating sorbitol pathway-linked neural and vascular dysfunction in rats with streptozocin-induced diabetes. 2-methyl-4-[N,N-dimethylsulfamoyl-piperazino]-pyrimidine (S-0773), a putative inhibitor of sorbitol dehydrogenase, was given in the drinking water to control and diabetic rats. After 5 weeks of diabetes, glycosylated hemoglobin levels were increased twofold and were unaffected by S-0773. Sorbitol levels in diabetic rats were increased 11- to 14-fold in ocular tissues and sciatic nerve; S-0773 increased sorbitol levels another 4-fold or more in these same tissues but had much smaller effects in other tissues. Diabetes-associated increases in fructose levels and lactate:pyruvate ratios in retina and in sciatic nerve were markedly attenuated by S-0773. S-0773 also attenuated, but did not completely normalize, impaired caudal nerve conduction and vascular dysfunction in ocular tissues, sciatic nerve, and aorta in diabetic rats. These observations, together with other evidence, suggest that sorbitol pathway-linked vascular dysfunction (in ocular tissues, peripheral nerve, and aorta) and electrophysiological dysfunction (in peripheral nerve) induced by diabetes are more closely linked to increased oxidation of sorbitol to fructose than to putative osmotic effects of elevated sorbitol levels or redox and metabolic imbalances associated with reduction of glucose to sorbitol by aldose reductase.

Animals↗
PubMed1990

Coordinated response of renal medullary enzymes regulating net sorbitol production in diuresis and antidiuresis.

The renal response to changes in hydration includes variation in intracellular sorbitol, a major inner medullary osmolyte. To examine the mechanism for changes in net sorbitol production, we measured activities of enzymes regulating sorbitol production (aldose reductase) and degradation (sorbitol dehydrogenase) in untreated, water diuretic, and antidiuretic (water restriction and/or vasopressin administration) rats. Collecting duct segments dissected from collagenase-treated kidneys of Sprague-Dawley rats were divided into outer medullary and three distinct inner medullary regions. Aldose reductase activity increased during antidiuresis and decreased during diuresis. In contrast, sorbitol dehydrogenase activity was very low during antidiuresis and increased during diuresis. These changes in enzyme activity were found after 3 days, but not after 1 day, of water diuresis/antidiuresis. Enzyme activity changed only in the deepest 50% of the inner medullary collecting duct. Thus, there is coordinated regulation of aldose reductase and sorbitol dehydrogenase activities so that (a) during water diuresis, aldose reductase activity decreases while sorbitol dehydrogenase activity increases; and (b) during antidiuresis (water restriction and/or vasopressin administration), aldose reductase activity increases while sorbitol dehydrogenase activity remains low. We conclude that long-term osmoregulation in response to physiologic stimuli involves both aldose reductase and sorbitol dehydrogenase activities in rat terminal inner medullary collecting duct segments.

Aldehyde Reductase↗
PubMed1987

Intestinal necrosis due to sodium polystyrene (Kayexalate) in sorbitol enemas: clinical and experimental support for the hypothesis.

Five patients who suffered catastrophic colonic necrosis are presented. All patients were uremic and received sodium polystyrene (Kayexalate) in sorbitol enemas for the treatment of hyperkalemia shortly before the development of signs and symptoms of colonic necrosis. In all specimens extensive ischemic necrosis was present, and Kayexalate crystals were noted in the intestinal lumen. Four of the five patients eventually died. To further investigate the occurrence of colonic necrosis after the administration of Kayexalate in sorbitol enemas, a series of experiments were performed in rats. Two groups of Sprague-Dawley rats were studied. One group was made uremic by performance of bilateral nephrectomy. The other group underwent sham operation. Enemas of saline, Kayexalate alone, sorbitol alone, or Kayexalate in sorbitol were administered. In nonuremic rats, transmural necrosis was noted in seven of 10 rats receiving sorbitol enemas and in six of 10 rats receiving Kayexalate in sorbitol enemas. No significant pathologic changes were noted in the rats receiving other enemas. In uremic rats, extensive transmural necrosis was noted in all rats receiving enemas of sorbitol or Kayexalate in sorbitol. All of these 19 rats died within the period of observation compared with no deaths in 18 rats that received enemas without sorbitol (p less than 0.001).

Adolescent↗
PubMed1979

Relationship of endogenous to dietary sorbitol. A study in normal and diabetic rats.

The relationship of endogenous to dietary sorbitol was investigated by measuring the sorbitol content of plasma, lens and kidney in normal an streptozotocin-injected rats fed for two-three weeks a control diet or a diet rich in either sorbitol or sucrose. The insulin content and secretory capacity of the pancreatic islets removed from these rats was also measured. In normal rats, the carbohydrate-rich diet increased the concentration of sorbitol in plasma but not lens or kidney. The carbohydrate-rich diet also increased the secretory responsiveness of the B-cell to glucose. Accumulation of sorbitol in lens and kidney occurred in diabetic rats. When the diabetic rats were treated with insulin, the sorbitol content of plasma and lens was less elevated than in untreated diabetic animals, despite poor control of the glycemia. The insulin treatment failed to prevent sorbitol accumulation in the kidney. There was no obvious difference between dietary sorbitol and sucrose respectively, in terms of sorbitol accumulation in tissues or stimulation of B-cell secretory potential.

Animals↗
PubMed2005

A potent sorbitol dehydrogenase inhibitor exacerbates sympathetic autonomic neuropathy in rats with streptozotocin-induced diabetes.

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.

Animals↗
PubMed1990

Sorbitol pathway activity and utilization of polyols in astroglia-rich primary cultures.

Astroglia-rich rat primary cultures can be grown in a glucose-free medium containing 25 mM sorbitol. After 10 days under these conditions, the total number of cells and DNA content are reduced to 50-60% of those of control cultures, but remain constant thereafter. The specific activities of the sorbitol pathway enzymes, sorbitol dehydrogenase and aldose reductase, are increased 2.5-fold and unchanged, respectively, if the cells are grown in the presence of sorbitol instead of glucose. Treatment with the aldose reductase inhibitor sorbinil does not decrease the number of cells cultured in the glucose-free medium in the presence of sorbitol. Fructose is as good a substrate for the glial cells as sorbitol, whereas out of a number of other polyols tested only xylitol can support the primary cultures for more than 3 days. Neither neuron-rich rat brain primary cultures nor rat glioma cells can be cultured in the sorbitol-containing medium in the absence of glucose. With sorbitol substituting for glucose in the culture medium, effects of glucose deprivation on cellular functions like sugar transport and metabolism can be investigated in glial cultures for an extended period of time.

Aldehyde Reductase↗
PubMed1984

Sorbitol accumulation is altered in type 1 (insulin-dependent) diabetes mellitus.

Intracellular sorbitol accumulation has been implicated as an aetiological factor for many of the complications of diabetes mellitus. Erythrocyte sorbitol is found in higher concentration in Type 1 (insulin-dependent) diabetic patients than in normal subjects. When sorbitol accumulation is corrected for its immediate precursor glucose (sorbitol/glucose ratio), the polyol accumulation remains significantly greater in erythrocytes from the Type 1 diabetic. Erythrocytes from Type 1 diabetic patients exposed to normal extracellular glucose concentrations for 3 h in vitro, accumulate more sorbitol and fructose than normal cells in the same incubation system. Near-normalization of plasma glucose in Type 1 diabetic patients for 12 h did not result in normal erythrocyte sorbitol levels. The increased sorbitol accumulation in erythrocytes from Type 1 diabetic subjects may reflect similar activity in the lens and nerve in long-standing diabetes. This increased sorbitol production was found in most, but not all, individuals with diabetes and appears to be an acquired characteristic. Those factors influencing enhanced tissue sorbitol accumulation may be important in the aetiology of diabetes-associated complications.

Adolescent↗
PubMed1989

Sorbitol metabolism in inner medullary collecting duct cells of diabetic rats.

Intracellular accumulation of sorbitol, generated from D-glucose via the aldose reductase pathway, is thought to play an important role in diabetic complications such as lens cataracts and neuropathy. In order to elucidate the effect of diabetes on the renal inner medulla, another sorbitol-rich tissue, male Wistar rats were treated with a single dose of streptozotocin (60 mg/kg body weight, i.p.). Six weeks later total inner medullary tissue (IM) or isolated inner medullary collecting duct (IMCD) cells were prepared. In diabetic IM tissue, sorbitol content was 1.8-fold higher than in control IM tissue (134 +/- 17 vs. 74 +/- 22 mumol/g tissue protein). Sorbitol production in both normal and diabetic IMCD cells was strongly dependent on extracellular D-glucose concentration. In normal cells, for example, sorbitol production was 90 +/- 9 mumol sorbitol/g protein x h at 45 mM D-glucose compared to 13 +/- 1 mumol/g protein x h at 5 mM. At identical D-glucose concentrations sorbitol synthesis in diabetic IMCD cells was, however, always significantly higher than in control cells (122% of control at 15 mM and 126% of control at 45 mM). In addition, aldose reductase activity in diabetic IM was found to be augmented. The maximal velocity was 4.2 times higher (97 +/- 22 U/g protein vs. 23 +/- 7 U/g protein) while the Km of the enzyme remained unchanged. Membrane permeability for sorbitol or the response to changes in extracellular osmolarity was not significantly different in diabetic IMCD cells and normal cells with correspondingly high intracellular sorbitol concentrations. Similarly the kinetic parameters of D-glucose uptake were not altered by streptozotocin treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Aldehyde Reductase↗
PubMed1983

The repressible metabolism of sorbitol (D-glucitol) by intact cells of the oral plaque-forming bacterium Streptococcus mutans.

Sorbitol metabolism of Streptococcus mutans was studied. Cocci adapted to growth in sorbitol, glucose or both were challenged to grow on and to ferment those carbohydrates in pH-controlled defined media with intact cells capable of metabolic inductions and regulations. Glucose degradation when in high concentration did not depend upon induction of glucose-specific phosphoenolpyruvate-dependent phosphotransferase activity, as it did at low glucose concentrations. Sorbitol utilization was signalled by the induction of sorbitol-specific phosphoenolpyruvate-dependent phosphotransferase and sorbitol-6-phosphate dehydrogenase activities which persisted throughout the growth cycle. However, when even low levels of glucose were present, sorbitol transport and catabolic activities were rapidly repressed and they were not de-repressed until essentially all glucose had been utilized. Metabolism of sorbitol thus relies on the sorbitol phosphotransferase/sorbitol-6-phosphate dehydrogenase pathway whose activity is sensitively repressed in the presence of glucose.

Enzyme Repression↗
PubMed1982

Regulation of NADPH-dependent mixed-function oxidation in perfused livers. Comparative studies with sorbitol and ethanol.

Sorbitol and ethanol were shown to have opposite effects on p-nitroanisole O-demethylation in perfused livers from fasted, phenobarbital-treated rats. Sorbitol (2 mM) stimulated drug metabolism by 50% while ethanol (20 mM) caused 80% inhibition. Both sorbitol and ethanol infusion decreased the NAD+/NADH ratio and increased fluorescence of pyridine nucleotides monitored from the liver surface; however, the NADP+/NADPH ratio was decreased by sorbitol but tended to be increased by ethanol. Stimulation of drug metabolism by sorbitol was abolished by pretreatment of fasted rats with 6-aminonicotinamide, an inhibitor of the pentose phosphate shunt, but was not affected by aminooxyacetate, a transaminase inhibitor. These results indicate that sorbitol stimulated p-nitroanisole metabolism by providing NADPH via the pentose phosphate shunt. Ethanol and sorbitol caused changes in intracellular concentrations of NADPH in livers from fasted rats which correlated directly with changes in hepatic levels of citrate and aspartate. Furthermore, aspartate infusion reduced the inhibition of p-nitroanisole O-demethylation by ethanol. This inhibition was also reversed partially by sorbitol in livers from 6-aminonicotinamide-treated rats. It is concluded that ethanol inhibits mixed-function oxidation primarily by decreasing the concentrations of citric acid cycle intermediates which leads to depletion of cytosolic NADPH.

Animals↗
PubMed1995

Tolrestat pharmacokinetic and pharmacodynamic effects on red blood cell sorbitol levels in normal volunteers and in patients with insulin-dependent diabetes.

OBJECTIVES: To examine the effect of diabetes mellitus on the pharmacokinetics of tolrestat and to investigate its effect on red blood cell sorbitol levels according to a new pharmacodynamic model for this class of drugs. METHODS: Single and multiple doses of tolrestat (200 mg/twice a day) were administered to 12 patients with insulin-dependent (type I) diabetes and 12 healthy volunteers in an open parallel trial. RESULTS: Tolrestat disposition was characterized by first-order absorption and biexponential disposition: In normal subjects the terminal disposition half-life (t1/2) was 13 +/- 3 hours (mean +/- SD) and the apparent oral clearance (CL/F) was 48 +/- 9 ml/hr/kg, similar to the values in patients with type I diabetes mellitus (t1/2 = 14 +/- 4 hours; CL/F = 55 +/- 10 ml/hr/kg). Red blood cell sorbitol concentrations, which declined because of tolrestat's inhibition of aldose reductase, were characterized by an indirect-response model including a 50% inhibition constant (IC50) for production of sorbitol by aldose reductase. The removal of sorbitol (kout) was slower in patients with diabetes. The plasma IC50 averaged 2.0 +/- 1.3 micrograms/ml in normal subjects and 2.5 +/- 1.9 micrograms/ml in patients with diabetes. IC50 values expressed in free (unbound) concentrations (fu = 0.64%), which ranged from 12 to 16 ng/ml, were similar to the in vitro IC50 for inhibition of sorbitol accumulation in human red blood cells. CONCLUSIONS: Tolrestat pharmacokinetics were similar in normal subjects and in patients with diabetes; however, the patients with diabetes had higher baseline sorbitol levels (11 versus 5 nmol/ml for normal subjects) and slower sorbitol efflux rates. The proposed biochemically realistic, dynamic model characterized well the red blood cell sorbitol response patterns after administration of single and multiple doses of tolrestat.

Adult↗
PubMed1993

Control of sorbitol metabolism in renal inner medulla of diabetic rats: regulation by substrate, cosubstrate and products of the aldose reductase reaction.

Streptozotocin diabetes induces a 4-fold increase in the maximal velocity of inner medullary aldose reductase as determined in vitro but increases sorbitol synthesis in intact inner medullary collecting duct (IMCD) cells only 1.3-fold. In order to resolve this discrepancy we investigated the importance of intracellular factors in controlling the role of cellular sorbitol synthesis. These factors include glucose concentration, sorbitol concentration, the activity of the NADPH-regenerating pentose phosphate pathway, intracellular NADP and NADPH content, and intracellular reduced (GSH) and oxidized glutathione (GSSG). It was found that the apparent Km of cellular sorbitol production for glucose was identical in control and diabetic rats (56 +/- 18 vs. 59 +/- 14 mmol/l D-glucose), whereas Vmax increased by 31% in diabetes. In inner medullary collecting duct cells of diabetic rats containing 146 +/- 5 mumol sorbitol/g protein, sorbitol synthesis was slightly lower (-15%), compared to cells which had been sorbitol-depleted prior to the experiment (87 +/- 4 mumol sorbitol/g protein). However, no inhibitory effect of sorbitol (up to 200 mmol/l) was observed on aldose reductase activity in vitro. In diabetic rats the content of NADPH was about 32% lower than in the control rats (3.8 +/- 0.3 vs. 5.6 +/- 0.4 mumol/g protein) and the ratio of NADPH/NADP was decreased from 25.6 +/- 5.1 to 8.6 +/- 1.7. In homogenates of the inner medulla the activity of 6-phospho-gluconate dehydrogenase (EC 1.1.1.43) was identical in both experimental groups, so the pentose phosphate shunt seems to be unaltered. GSH content in diabetic rats was also diminished (4.02 +/- 0.67 mumol/g protein vs. 7.41 +/- 0.5 mumol/g protein) and the GSH/GSSG ratio fell from 92.6 to 57.4. In enzyme tests in vitro an apparent Km of 7.3 +/- 1.9 mumol/l of the aldose reductase for NADPH was found; NADP acted as competitive inhibitor with an apparent K(i) of 183 +/- 31 mumol/l. Aldose reductase activity was also found to be strongly inhibited by the SH-group reagent p-chloromercurybenzoesulfonate (apparent K(i) = 0.85 x 10(-6) mol/l). Combining the results obtained on the properties of the aldose reductase in vitro and the observation made in the intact cells, the investigators suggest that the decrease in NADPH/NADP ratio, as well as changes in the redox state in the cells of diabetic animals, can play a significant role in the control of sorbitol synthesis.

Aldehyde Reductase↗