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PubMed1991

Enhanced lipolysis in 3T3-L1 adipocytes following prolonged exposure to tolbutamide.

The effect of tolbutamide on lipolysis was examined in 3T3-L1 adipocytes. Whereas lipolysis was reversibly inhibited by tolbutamide, prolonged treatment with this agent dose-dependently increased both basal and isoproterenol-stimulated lipolysis in washed adipocytes. The latter effect of tolbutamide was not accompanied with altered cAMP levels in the cells and was abolished in the presence of cycloheximide. Moreover, the lipolytic responses induced by isobutylmethylxanthine, forskolin and dibutyryl cAMP were also augmented by prolonged treatment of adipocytes with tolbutamide. Thus, it appears that development of enhanced lipolysis in 3T3-L1 adipocytes following prolonged exposure to tolbutamide requires continuous protein synthesis and probably involves a step distal to cAMP production.

1-Methyl-3-isobutylxanthine↗

PubMed1982

Effects of tolbutamide on insulin binding to isolated fat cells of the rat.

In isolated fat cells of the rat the in vitro and in vivo effects of tolbutamide on insulin binding and insulin response were studied. 450 mg tolbutamide/kg/day given for 7 days significantly increased the binding of insulin to isolated adipocytes. The binding curves reflected an increase in the number of receptor sites rater than in the affinity. The effect was associated with an enhanced response to insulin of the adipose tissue, since the fat cells obtained from animals treated with tolbutamide converted significantly more glucose to lipids in the presence of insulin than those obtained from the control group. However, the augmentation of insulin binding sites was observed only at a large tolbutamide dosage, which reduced the pancreatic insulin content, the secretory response of the isolated pancreas, and the serum insulin levels. Smaller doses, sufficient to produce metabolic effects via a stimulation of insulin secretion, did not provide additional insulin binding sites. When added in vitro to the binding assay or to adipose tissue incubated for 16 h, tolbutamide failed to increase insulin binding of the fat cells. It is suggested, therefore, that the effects produced by tolbutamide after in vivo treatment reflect an indirect rather than a direct action of the sulphonylurea.

Adipose Tissue↗

PubMed1993

The hypoglycemic sulphonylurea tolbutamide increases N-methyl-D-aspartate- but not kainate-activated currents in hippocampal neurons in culture.

The effects of the hypoglycemic sulphonylurea tolbutamide, a marker of K(+)-ATP channels, on the N-methyl-D-aspartate- (NMDA) and kainate-activated currents were studied in rat hippocampal neurons in culture, using the patch-clamp technique in a whole-cell configuration. Tolbutamide (500 microM) reversibly increased the peak amplitude and the steady state level of NMDA- but not kainate-evoked currents. This effect was not glycine dependent as it was observed at low and saturated concentrations of glycine. The affinity of the NMDA receptor-channel complex for glycine did not change in the presence of tolbutamide. The action of tolbutamide on the NMDA-activated current was not mediated by K(+)-ATP channels since CsCl was added intracellularly at concentrations which completely blocked all K+ channels. Possible mechanisms explaining the effect of tolbutamide via the modulation of intracellular messengers are discussed.

Animals↗

PubMed1988

Cytosolic ADP enhances the sensitivity to tolbutamide of ATP-dependent K+ channels from pancreatic B-cells.

The effects of intracellular purine nucleotides on tolbutamide-induced block of ATP-dependent K+ channels from mouse pancreatic B-cells were studied using the patch-clamp technique. When applied to the inside of excised patches, tolbutamide alone blocked channel activity half-maximally at 55 microM and the concentration-response curve for the inhibition of K+ channels by tolbutamide was flat. ADP (1 mM), but not other nucleotides (AMP, GTP or GDP) increased the steepness of the concentration-response curve and decreased the half-maximally effective tolbutamide concentration to 4.2 microM. It is suggested that the ATP-dependent K+ channel or a closely related structure contains a receptor which is accessible for cytosolic ADP and controls the sensitivity to tolbutamide.

Adenosine Diphosphate↗

PubMed1994

Evidence that tolbutamide induces prolactin secretion by a mechanism which does not involve blocking ATP-sensitive potassium channels.

Tolbutamide is an important member of the sulfonylureas, drugs which stimulate secretion of several hormones, including insulin and prolactin (PRL), through a mechanism postulated to involve blocking ATP-sensitive K+ channels. In the present study, we have evaluated the hypothesis relating the induced secretion to an effect on K+ channels by examining the effect of tolbutamide and the ATP-sensitive K+ channel-opener, diazoxide, on PRL secretion by acutely dispersed perifused adenohypophyseal cells from young adult male rats. Five-min perifusion of 0.1-50 microM tolbutamide induced a concentration-correlated secretion of PRL with a minimum effective concentration of 0.1 microM. Both basal and 50 microM tolbutamide-induced PRL secretion were significantly suppressed by 10 microM dopamine or 2 microM nifedipine, which block Ca2+ influx through L-type channels, but not by 100 microM diazoxide, indicating that tolbutamide induces PRL secretion by a mechanism involving Ca2+ influx through L-type Ca2+ channels which is not related to its ability to block ATP-sensitive K+ channels.

Adenosine Triphosphate↗

PubMed1977

Onset and reversibility of changes in secretory function and composition of isolated rat pancreatic islets following long-term administrationof high or low tolbutamide doses.

Chronic administration of a high tolbutamide dose to rats induces islet hypertrophy associated with a decreased insulin content per islet and with a diminished insulin release in response to a glucose or leucine stimulus. These changes are reversible after discontinuation of tolbutamide. Chronic administration of a low tolbutamide dose (effective on islet size, on insulin content per islet, or on leucine-induced insulin release is normal in the presence of glucagon (5 mug/ml) or theophylline (5 mM). Since islet hypertrophy occurs following administration of high tolbutamide doses only and is associated with hypofunction rather than with hyperfunction, it seems hardly conceivable that the therapeutic principle of tolbutamide is based on a beta-cytotrophic effect. B-cell hypofunction seems to be due to at least three factors: the decrease in the insulin content per islet, an impairement in secretory signal recognition, and an interference with the process of signal transmission.

Animals↗

PubMed1979

Insulin secretory dynamics after two consecutive intravenous stimulations with glucose and/or tolbutamide.

Intravenous glucose and/or tolbutamide administered in two consecutive pulses 30 and 60 min apart to the same subjects using identical doses showed that insulin secretory responses was altered during a subsequent stimulation and that this was modulated by the time factor. Insulin response was more sustained after the second glucose pulses and the insulin peak response was delayed and diminished if the second glucose dose was given 30 min after the first, but not if given 60 min later. It is suggested that the beta-cell membrane might remain partially depolarized above a certain glucose level or that a postulated signal relay mechanism might become saturated. Responses to two tolbutamide pulses did not show these characteristics; however, the second insulin response was smaller than the first. When the first pulse was glucose and the second tolbutamide, or vice versa, the second responses were altogether different from those elicited by the double doses of either tolbutamide or glucose. To explain these characteristic patterns of insulin secretory dynamics, the existence of occult glucose receptors on the beta-cell that are opened up by tolbutamide was postulated. These studies do not support the two-pool theory, or at least restrict it to glucose-stimulated insulin response. The positive correlations between the first and the second insulin responses in all tests argue strongly against the existence of an insulin feedback mechanism in man.

Adult↗

PubMed1992

Effects of tolbutamide on fructose-2,6-bisphosphate formation and ketogenesis in hepatocytes from diabetic rats.

To assess the extrapancreatic action of sulfonylurea directly in the diabetic, effects of tolbutamide on hepatocyte fructose-2,6-bisphosphate (F-2,6-P2) formation and ketone production were investigated using isolated hepatocytes from streptozotocin (STZ)-induced diabetic rats. The basal level of hepatocyte F-2,6-P2 was significantly higher in diabetic rats within 2 weeks after STZ (40 mg/kg body weight) injection compared with that in the nondiabetic control group. Ultimately, a marked decrease in the F-2,6-P2 level was observed at 4 weeks after STZ administration (10% of the control). Although the addition of tolbutamide further increased the hepatocyte F-2,6-P2 level during the first week after STZ injection, no significant effect was observed after the second week and on from the initial STZ. Treatment of diabetes with insulin restored the stimulatory effect of tolbutamide on the hepatocyte F-2,6-P2 formation. Tolbutamide, independently of insulin treatment, lowered the ketone production of hepatocytes from diabetic rats. The present results indicate that insulin is necessary, in advance, for sulfonylurea to stimulate the liver F-2,6-P2 formation, while tolbutamide inhibition of hepatocyte ketone production is independent of insulin. These results provide further support for the role of sulfonylurea in regulating hepatic energy metabolism in the diabetic.

3-Hydroxybutyric Acid↗

PubMed1985

Effect of tolbutamide and chlorpropamide on acetaldehyde metabolism in two inbred strains of mice.

The mechanisms by which chlorpropamide and tolbutamide disrupt acetaldehyde metabolism were studied in C57BL and DBA mice. Acute po administration of varying doses of tolbutamide or chlorpropamide 2.5 hr before a 3.0 g/kg ip dose of ethanol to C57BL and DBA mice resulted in significant elevations of blood acetaldehyde when measured 2.5 hr after ethanol dosing. Dose-response analysis revealed a significant (p less than .05) difference in ED50 values for the elevated blood acetaldehyde response to tolbutamide in DBA (60 mg/kg) and C57BL (100 mg/kg) mice. The ED50 value for potentiation by chlorpropamide of blood acetaldehyde concentration was similar (23 to 32 mg/kg) in both inbred strains. At higher doses of chlorpropamide, DBA mice displayed elevations of blood acetaldehyde nearly threefold greater than those measured in C57BL mice treated identically. Measurements of aldehyde dehydrogenase (ALDH) in hepatic subcellular fractions, obtained from both inbred strains treated with 100 mg/kg tolbutamide or chlorpropamide prior to a 3.0 g/kg dose of ethanol, revealed a 50 to 80% inhibition of the low-Km ALDH present in mitochondria. Chlorpropamide and tolbutamide did not inhibit ALDH in vitro, suggesting that metabolites of these hypoglycemic agents may be responsible for the genotypic-dependent alterations in in vivo acetaldehyde oxidation.

Acetaldehyde↗

PubMed1986

Effect of tolbutamide on fructose-6-phosphate,2-kinase and fructose-2,6-bisphosphatase in rat liver.

The effects of tolbutamide on the activities of fructose-6-phosphate,2-kinase and fructose-2,6-bisphosphatase were examined using rat hepatocytes. Tolbutamide stimulated fructose-6-phosphate,2-kinase activity and inhibited fructose-2,6-bisphosphatase activity, resulting in an increase of fructose-2,6-bisphosphate level. Changes in the activities of the enzyme by tolbutamide were due to variation in the Km value, but not dependent on alteration of Vmax. Glucagon inhibition of fructose-2,6-bisphosphate formation resulting from an inactivation of fructose-6-phosphate,2-kinase and an activation of fructose-2,6-bisphosphatase was released by tolbutamide. Tolbutamide stimulation of fructose-2,6-bisphosphate formation through regulation of fructose-6-phosphate,2-kinase/fructose-2,6-bisphosphatase may produce enhancement of glycolysis and inhibition of gluconeogenesis in the liver.

Animals↗

PubMed2001

Desensitization of insulin secretory response to imidazolines, tolbutamide, and quinine. I. Secretory and morphological studies.

The desensitization of pancreatic B-cells against stimulation by insulin secretagogues that inhibit ATP-dependent K(+) channels (K(ATP) channels) was investigated by measuring insulin secretion of perifused pancreatic islets. Additionally, the islet insulin content and the number of secretory granules per B-cell were determined. Prior to the measurement of secretion, islets were cultured for 18 h in the presence or absence of the test agents in a cell-culture medium containing 5 mM glucose. The effects of three imidazolines, phentolamine, alinidine, and idazoxan (100 microM each) were compared with those of the well-characterized sulfonylurea, tolbutamide (500 microM), and those of the ion channel-blocking alkaloid, quinine (100 microM). Insulin secretion was strongly reduced upon re-exposure to phentolamine, alinidine, tolbutamide, and quinine, whereas idazoxan, which stimulated secretion only weakly, had no significant effect. The imidazoline secretagogues phentolamine and alinidine induced a cross-desensitization against the stimulatory effect of tolbutamide and quinine. A long-term depolarization with 40 mM KCl was also able to induce a significant reduction of the secretory response to all of the above secretagogues. The insulin content of cultured islets was moderately, but significantly reduced by alinidine, whereas the reduction by phentolamine, tolbutamide, and quinine was not significant. In contrast to these observations, the ultrastructural examination revealed that tolbutamide-treated B-cells had a high degree of degranulation, whereas the other test agents and 40 mM KCl produced only a partial degranulation, except for phentolamine, which produced no significant degranulation at all. These results suggest that the desensitization of insulin secretion is a common property of all agents that stimulate insulin secretion by depolarisation of the plasma membrane. Depending on the specific secretagogue, additional mechanisms, proximal and distal to Ca(2+) influx, appear to contribute to the desensitization (see Rustenbeck et al., pages 1695-1703, this issue).

Animals↗

PubMed1998

Tolbutamide attenuates diazoxide-induced aggravation of hypoxic cell injury.

ATP-dependent potassium (KATP) channels of neurons are closed in the presence of physiological levels of intracellular ATP and open when ATP is depleted during hypoxia or metabolic damage. The present study investigates hypoxic alterations of purine and pyrimidine nucleotide levels supposed to intracellularly modulate KATP channels. In addition, the effects of the KATP channel activator diazoxide and its antagonist tolbutamide were investigated on ATP, GTP, CTP and UTP levels in slices of the parietal cortex. Hypoxia was evoked by saturation of the medium with 95% N2-5% CO2 instead of 95% O2-5% CO2 for 5 min. Nucleotide contents were measured by anion-exchange HPLC in neutralized perchloric acid extracts obtained from slices frozen immediately at the end of incubation. Hypoxia per se decreased purine and pyrimidine nucleoside triphosphate contents. Thus, ATP and GTP contents were reduced to 69.9 and 77.6% of the respective normoxic levels. UTP and CTP contents were even more decreased (to 60.9 and 41.6%),, probably because the salvage pathway of these pyrimidine nucleotides is less effective than that of the purine nucleotides ATP and GTP. While tolbutamide (30 microM) had no effect on the hypoxia-induced decrease of nucleotides, diazoxide at 300, but not 30 microM aggravated the decline of ATP, UTP and CTP to 51.8, 37.5 and 28.5% of the contents observed at normoxia; GTP levels also showed a tendency to decrease after diazoxide application. Tolbutamide (300 microM) antagonized the effects of diazoxide (300 but not 30 microM aggravated the decline of ATP, UTP and CTP to 51.8, 37.5 and 28.5% of the contents observed at normoxia; GTP levels also showed a tendency to decrease after diazoxide application. Tolbutamide (300 microM) antagonized the effects of diazoxide (300 MicroM). Nucleoside diphosphate (ADP, GDP and UDP) levels were uniformly increased by hypoxia. There was no hypoxia-induced increase of ADP contents in the presence of tolbutamide (300 microM). The ATP/ADP, GTP/GDP and UTP/UDP ratios uniformly declined at a low pO2. However, only the ATP/ADP ratio was decreased further by diazoxide (300 microM). The observed alterations in nucleotide contents may be of importance for long- and short-term processes related to acute cerebral hypoxia. Thus, hypoxia-induced alterations of purine and pyrimidine nucleotide levels may influence the open state of KATP-channels during the period of reversible hypoxic cerebral injury. Furthermore, alterations during the irreversible period of cerebral injury may also arise, as a consequence of decreased pyrimidine nucleotide contents affecting cell survival viaprotein and DNA synthesis.

Animals↗

PubMed2001

Proliferation of C6 glioma cells is blunted by the increase in gap junction communication caused by tolbutamide.

We have previously reported that tolbutamide prevents the inhibition of gap junction communication in astrocytes. Here, we show that tolbutamide increases gap junction communication and connexin 43 expression in poorly coupled C6 glioma cells. The increase in communication is concurrent with the inhibition of the rate of proliferation due to a block of the progression of C6 glioma cells through the S phase of the cell cycle. The effects of tolbutamide were quantitatively similar to that found after the elevation of intracellular cAMP. Furthermore, the effects of tolbutamide and cAMP were additive. The possible beneficial effect of tolbutamide on gene therapy for gliomas is discussed.

Animals↗

PubMed2000

Characterisation of tolbutamide hydroxylase activity in the common brushtail possum, (Trichosurus vulpecula) and koala (Phascolarctos cinereus): inhibition by the eucalyptus terpene 1,8-cineole.

Plant constituents such as terpenes are major constituents of the essential oil in Eucalyptus sp. 1,8-Cineole and p-cymene (Terpenes present in high amounts in Eucalyptus leaves) are potential substrates for the CYP family of enzymes. We have investigated tolbutamide hydroxylase as a probe substrate reaction in both koala and terpene pretreated and control brushtail possum liver microsomes and examined inhibition of this reaction by Eucalyptus terpenes. The specific activity determined for tolbutamide hydroxylase in the terpene treated brushtails was significantly higher than that for the control animals (1865+/-334 nmol/mg microsomal protein per min versus 895+/-27 nmol/mg microsomal protein per min). The activity determined in koala microsomes was 8159+/-370 nmol/mg microsomal protein per min. Vmax values and Km values for the terpene treated possum, control, possum and koala were 1932-2225 nmol/mg microsomal protein per min and 0.80 0.81 mM; 1406-1484 nmol/mg microsomal protein per min and 0.87-0.92 mM and 5895-6403 nmol/mg microsomal protein per min and 0.067-0.071 mM, respectively. Terpenes were examined as potential inhibitors of tolbutamide hydroxylase activity. 1,8-Cineole was found to be a competitive inhibitor for the enzyme responsible for tolbutamide hydroxylation (Ki 15 microM) in the possum. In koala liver microsomes stimulation of tolbutamide hydroxylase activity was observed when concentrations of cineole were increased. Therefore, although inhibition was observed, the type of inhibition could not be determined.

Animals↗

PubMed1989

Expression of a human liver cytochrome P-450 protein with tolbutamide hydroxylase activity in Saccharomyces cerevisiae.

The human liver cytochrome P-450 (P-450) proteins responsible for catalyzing the oxidation of mephenytoin, tolbutamide, and hexobarbital are encoded by a multigene family (CYP2C). Although several cDNA clones and proteins related to this "P-450MP" family have been isolated, assignment of specific catalytic activities remains uncertain. Sulfaphenazole was found to inhibit tolbutamide hydroxylation to a greater extent than mephenytoin or hexobarbital hydroxylation. The inhibition by sulfaphenazole was competitive for tolbutamide and hexobarbital hydroxylation but with much different Ki values (5 vs 480 microM, respectively). Inhibition of mephenytoin hydroxylase was not competitive. The results suggest that different P-450 proteins in the P450MP family may be involved in the metabolism of these compounds. A cDNA clone (MP-8) related to the P-450MP family, isolated from a bacteriophage lambda gt11 human liver library, was expressed in Saccharomyces cerevisiae by using the pAAH5 expression vector. Yeast transformed with pAAH5 containing the MP-8 sequence (pAAH5/MP-8) showed a ferrous-CO spectrum typical of the P-450 proteins. Immunoblotting with anti-P450MP revealed that pAAH5/MP-8 microsomes contained a protein with an Mr similar to that of P-450MP-1 (approximately 48,000) that was not present in microsomes from yeast transformed with pAAH5 alone (1.7 X 10(4) molecules of the expressed P-450 per cell). Microsomes from pAAH5/MP-8 contained no detectable mephenytoin 4'-hydroxylase activity but were more active in tolbutamide hydroxylation, on a nanomoles of P-450 basis, than human liver microsomes. The pAAH5/MP-8 microsomes also contained hexobarbital 3'-hydroxylase activity, although the enrichment compared to liver microsomes was not great with respect to the tolbutamide hydroxylase activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Catalysis↗

PubMed1982

Effects of total plasma concentration and age on tolbutamide plasma protein binding.

Tolbutamide plasma protein binding at different total tolbutamide concentrations was determined in 44 healthy, nonsmoking, drug-free men from 23 to 87 yr old. The data showed that unbound drug increased with total tolbutamide plasma concentration and with age, but that neither the binding equilibrium constant nor the number of binding sites correlated with age. The increase in unbound fraction with age could be partially explained by the decrease in albumin concentration in elderly subjects. Results of multiple linear regression analysis indicated that, although age had a considerably greater influence than albumin concentration, total tolbutamide concentration was the most important determinant of the unbound fraction. Thus, both age and total plasma concentration may affect tolbutamide kinetics.

Adult↗

PubMed1996

Effects of tolbutamide on vascular ATP-sensitive potassium channels in humans. Comparison with literature data on glibenclamide and glimepiride.

Sulfonylurea (SU) derivatives exert their hypoglycemic effect by blockade of adenosine-5'-triphosphate-sensitive potassium (KATP) channels in the beta-cell of the pancreas. Interestingly, KATP channels also occur in the cardiovascular system, where they are thought to play an important role in cardioprotective mechanisms against ischemia. We have recently shown that the classical second generation SU-derivative glibenclamide is able to block vascular KATP channels in man, whereas the newly developed second generation derivative glimepiride was devoid of this property. The aim of this study was to determine whether the first generation SU derivative tolbutamide has KATP channel blocking properties in humans. In a group of 12 healthy male non-smoking volunteers, we investigated whether therapeutic concentrations of tolbutamide were able to inhibit the forearm vasodilation in response to the infusion of the KATP channel opening drug diazoxide into the brachial artery. Changes in forearm blood flow were recorded by venous occlusion mercury-in-silastic strain-gauge plethysmography. Diazoxide alone increased the forearm blood flow ratio dose-dependently by ultimately 691 +/- 198%. A second diazoxide infusion in the presence of tolbutamide revealed a comparable vasodilator response with a percentage increase in forearm blood flow ratio of ultimately 542 +/- 111%. This response did not differ from the vasodilator response to diazoxide alone. The present study shows that therapeutic concentrations of tolbutamide are not able to attenuate the vasodilation caused by the KATP channel opener diazoxide in man. When compared with published data on second generation SU derivatives, tolbutamide shows an intermediate position between glibenclamide (with significant blockade of vascular KATP channels) versus glimepiride (with no blockade at all). It remains to be determined whether these acute effects of SU derivatives on pharmacological opening of forearm vascular KATP channels can be extrapolated to the chronic effects of these drugs on ischemia-mediated opening of myocardial KATP channels during treatment of NIDDM patients.

Adenosine Triphosphate↗

PubMed1998

Roles of two allelic variants (Arg144Cys and Ile359Leu) of cytochrome P4502C9 in the oxidation of tolbutamide and warfarin by human liver microsomes.

1. Tolbutamide methyl hydroxylation and racemic warfarin 7-hydroxylation activities were determined in liver microsomes of 39 Japanese and 45 Caucasians genotyped for the cytochrome P450 (P450 or CYP) 2C9 gene into three groups, namely the wild-type (Arg144.Ile359), and two heterozygous Cys allele (Cys144.Ile359) and Leu allele (Arg144.Leu359) variants. 2. Good correlations were found between tolbutamide methyl hydroxylation and racemic warfarin 7-hydroxylation activities in liver microsomes of Japanese and Caucasians. Humans with the Cys allele CYP2C9 variant, which was detected in 22% of Caucasians, were found to have similar catalytic rates to those of the wild-type in the oxidations of tolbutamide and racemic warfarin, whereas humans with the Leu allele, which was detected in 8% Japanese and 7% Caucasian samples, had lower catalytic rates than those of other two groups. 3. The rates of 6- and 7-hydroxylation of racemic warfarin were correlated well with those of S-warfarin, but not R-warfarin, in human liver microsomes. 4. Both human liver microsomes and recombinant CYP2C9 catalysed 7-hydroxylation of S-warfarin more extensively than those of R-warfarin. K(m)'s for the 7-hydroxylation of S-warfarin were not very different in liver microsomes of humans with these three genotypes. Anti-CYP2C9 antibodies and sulphaphenazole inhibited the 6- and 7-hydroxylation of S-warfarin, but not R-warfarin, by > 90% and the methyl hydroxylation of tolbutamide by about 50%. 5. These results suggest that humans with Leu allele of CYP2C9 have lower Vmax's for S-warfarin 7-hydroxylation and tolbutamide methyl hydroxylation than those with wild-type and Cys allele CYP2C9, although the K(m)'s are not very different in liver microsomes of these three groups of humans. R-warfarin hydroxylation may be catalysed by P450 enzymes other than CYP2C9 in man.

Alleles↗