Involvement of Phosphorylase Kinase Inhibition in the Effect of Resorcinol and Proglycosyn on Glycogen Metabolism in the Liver

Schaftingen, Emile Van

doi:10.1111/j.1432-1033.1995.301_c.x

Cited by 14 publications

(23 citation statements)

References 33 publications

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“…To confirm that UDP-glucuronate was the precursor for the formation of glucuronate, we checked whether resorcinol, a readily glucuronidated phenol derivative (21), and D-galactosamine, which traps uridine nucleotides as UDP-galactosamine and derivatives of it (22), would inhibit the formation of glucuronate induced by aminopyrine in the presence of sorbinil. As shown in Table I, both agents depleted UDP-glucuronate, and in the case of galactosamine, also UDP-glucose.…”

Section: Analysis Of the Effect Of Aminopyrine-mentioning

confidence: 99%

Rapid Stimulation of Free Glucuronate Formation by Non-glucuronidable Xenobiotics in Isolated Rat Hepatocytes

Linster¹,

Schaftingen

2003

Journal of Biological Chemistry

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Vitamin C synthesis in rat liver is enhanced by several xenobiotics, including aminopyrine and chloretone. The effect of these agents has been linked to induction of enzymes potentially involved in the formation of glucuronate, a precursor of vitamin C. Using isolated rat hepatocytes as a model, we show that a series of agents (aminopyrine, antipyrine, chloretone, clotrimazole, metyrapone, proadifen, and barbital) induced in a few minutes an up to 15-fold increase in the formation of glucuronate, which was best observed in the presence of sorbinil, an inhibitor of glucuronate reductase. They also caused an ϳ2-fold decrease in the concentration of UDP-glucuronate but little if any change in the concentration of UDP-glucose. Depletion of UDP-glucuronate with resorcinol or D-galactosamine markedly decreased the formation of glucuronate both in the presence and in the absence of aminopyrine, confirming the precursorproduct relationship between UDP-glucuronate and free glucuronate. Most of the agents did not induce the formation of detectable amounts of glucuronides, indicating that the formation of glucuronate is not due to a glucuronidation-deglucuronidation cycle. With the exception of barbital (which inhibits glucuronate reductase), all of the above mentioned agents also caused an increase in the concentration of ascorbic acid. They had little effect on glutathione concentration, and their effect on glucuronate and vitamin C formation was not mimicked by glutathione-depleting agents such as diamide and buthionine sulfoximine. It is concluded that the stimulation of vitamin C synthesis exerted by some xenobiotics is mediated through a rapid increase in the conversion of UDP-glucuronate to glucuronate, which does not apparently involve a glucuronidation-deglucuronidation cycle.Vitamin C synthesis, which takes place in the liver of most mammalian species, starts with the formation of free glucuronate from UDP-glucuronate, possibly via glucuronate 1-phosphate as an intermediate (Fig. 1). Reduction and lactonization, probably in this order, lead to the formation of L-gulono-1,4-lactone, which is oxidized to ascorbic acid by L-gulonolactone oxidase, an enzyme associated to the endoplasmic reticulum membrane (reviewed in Ref. 1). This enzyme is absent in several species including humans and guinea pig, for which ascorbic acid is therefore a vitamin. L-gulonate can also be converted in the liver to L-xylulose, through the successive action of L-gulonate 3-dehydrogenase and 3-dehydro-L-gulonate decarboxylase. L-xylulose is then channeled to gluconeogenesis by being converted to xylitol by NADPH-dependent L-xylulose reductase and then to D-xylulose by D-xylulose reductase, a NADdependent enzyme. Deficiency in the first of these two enzymes results in a benign condition known as essential pentosuria (reviewed in Ref. 2).It has been known for several decades that the administration to rats of various drugs such as barbiturates, chloretone, and aminopyrine markedly stimulates the formation and the urinary excretion of vitamin...

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Section: Analysis Of the Effect Of Aminopyrine-mentioning

confidence: 99%

Rapid Stimulation of Free Glucuronate Formation by Non-glucuronidable Xenobiotics in Isolated Rat Hepatocytes

Linster¹,

Schaftingen

2003

Journal of Biological Chemistry

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“…Two other cdk inhibitors, purvanalol and kenpaullone (36), also attenuated the glycogenic stimulation by methyl-5HT (not shown). Roscovitine counteracted the inactivation of GPa by 5-HT and methyl-5HT but not by resorcinol, an indirect inhibitor of Phk (38) or the GPI (Fig. 6 B ).…”

Section: Resultsmentioning

confidence: 92%

A Novel Mechanism for Regulating Hepatic Glycogen Synthesis Involving Serotonin and Cyclin-Dependent Kinase-5

et al. 2011

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Hepatic autonomic nerves regulate postprandial hepatic glucose uptake, but the signaling pathways remain unknown. We tested the hypothesis that serotonin (5-hydroxytryptamine [5-HT]) exerts stimulatory and inhibitory effects on hepatic glucose disposal. Ligands of diverse 5-HT receptors were used to identify signaling pathway(s) regulating glucose metabolism in hepatocytes. 5-HT had stimulatory and inhibitory effects on glycogen synthesis in hepatocytes mediated by 5-HT1/2A and 5-HT2B receptors, respectively. Agonists of 5-HT1/2A receptors lowered blood glucose and increased hepatic glycogen after oral glucose loading and also stimulated glycogen synthesis in freshly isolated hepatocytes with greater efficacy than 5-HT. This effect was blocked by olanzapine, an antagonist of 5-HT1/2A receptors. It was mediated by activation of phosphorylase phosphatase, inactivation of glycogen phosphorylase, and activation of glycogen synthase. Unlike insulin action, it was not associated with stimulation of glycolysis and was counteracted by cyclin-dependent kinase (cdk) inhibitors. A role for cdk5 was supported by adaptive changes in the coactivator protein p35 and by elevated glycogen synthesis during overexpression of p35/cdk5. These results support a novel mechanism for serotonin stimulation of hepatic glycogenesis involving cdk5. The opposing effects of serotonin, mediated by distinct 5-HT receptors, could explain why drugs targeting serotonin function can cause either diabetes or hypoglycemia in humans.

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“…The inactivation of phosphorylase caused by α-methyl-5-HT is unlikely to be due to changes in concentrations of endogenous ligands of phosphorylase because of the unchanged cell content of glucose 6-phosphate and the lack of synergy with the indole carboxamide inhibitor [31]. The metabolic effects of α-methyl-5-HT in hepatocytes show various similarities to the actions of the antidiabetic drug proglycosyn and its analogue resorcinol, which cause inactivation of phosphorylase, in part through inhibition of phosphorylase kinase [32]. A decrease in phosphorylase kinase activity may also be involved in the inactivation of phosphorylase by α-methyl-5-HT, as shown by the slower rate of activation of phosphorylase during inhibition of protein phosphatases.…”

Section: Discussionmentioning

confidence: 99%

“…However, α-methyl-5-HT did not affect the affinity (EC 50 ) for CP-91149 (control, 1.56±0.04 μmol/l; 10 μmol/l Me-5-HT, 1.40±0.13 μmol/l; means±SEM, n=4), suggesting that phosphorylase inactivation by α-methyl-5-HT is unlikely to be due to altered concentrations of phosphorylase ligands. Because the metabolic actions of α-methyl-5-HT share similarities with the antihyperglycaemic drug proglycosyn and its analogue resorcinol [32], which stimulate glycogen synthesis and inactivate phosphorylase but do not stimulate glycolysis, we tested the combined effects of resorcinol and α-methyl-5-HT on phosphorylase a. Resorcinol caused inactivation of phosphorylase a with half-maximal effect at ∼10 μmol/l. The effects of submaximal concentrations of α-methyl-5-HT and resorcinol were additive but not synergistic and α-methyl-5-HT did not affect the affinity for resorcinol (EC 50 , 12.2±0.9 vs 9.4±0.6 μmol/l).…”

Section: -mentioning

confidence: 99%

“…The inactivation of phosphorylase by proglycosyn and resorcinol is due, at least in part, to inhibition of phosphorylase kinase [32]. We therefore tested whether α-methyl-5-HT affects phosphorylase kinase activity by determining the time course of activation of phosphorylase in hepatocytes after addition of calyculin A, an inhibitor of type-1 and type-2A protein phosphatases (Fig.…”

Section: -mentioning

confidence: 99%

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Stimulation of glycogen synthesis and inactivation of phosphorylase in hepatocytes by serotonergic mechanisms, and counter-regulation by atypical antipsychotic drugs

2007

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Aims/hypothesis Intraportal infusion of serotonin (5-hydroxytryptamine, 5-HT) or inhibitors of its cellular uptake stimulate hepatic glucose uptake in vivo by either direct or indirect mechanisms. The aims of this study were to determine the direct effects of 5-HT in hepatocytes and to test the hypothesis that atypical antipsychotic drugs that predispose to type 2 diabetes counter-regulate the effects of 5-HT. Materials and methods Rat hepatocytes were studied in short-term primary culture. Results Serotonin (5-HT) stimulated glycogen synthesis at nanomolar concentrations but inhibited it at micromolar concentrations. The stimulatory effect was mimicked by α-methyl-5-HT, a mixed 5-HT1/5-HT2 receptor agonist, whereas the inhibition was counteracted by a 5-HT2B/2C receptor antagonist. α-Methyl-5-HT stimulated glycogen synthesis additively with insulin, but unlike insulin, did not stimulate glucose phosphorylation and glycolysis, nor did it cause Akt (protein kinase B) phosphorylation. Stimulation of glycogen synthesis by α-methyl-5-HT correlated with depletion of phosphorylase a. This effect could not be explained by elevated levels of glucose 6-phosphate, which causes inactivation of phosphorylase, but was explained, at least in part, by decreased phosphorylase kinase activity in situ. The antipsychotic drugs clozapine and olanzapine, which bind to 5-HT receptors, counteracted the effect of α-methyl-5-HT on phosphorylase inactivation. Conclusions/interpretation This study provides evidence for both stimulation and inhibition of glycogen synthesis in hepatocytes by serotonergic mechanisms. The former effects are associated with the inactivation of phosphorylase and are counteracted by atypical antipsychotic drugs that cause hepatic insulin resistance. Antagonism of hepatic serotonergic mechanisms may be a component of the hepatic dysregulation caused by antipsychotic drugs that predispose to type 2 diabetes.

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Involvement of Phosphorylase Kinase Inhibition in the Effect of Resorcinol and Proglycosyn on Glycogen Metabolism in the Liver

Cited by 14 publications

References 33 publications

Rapid Stimulation of Free Glucuronate Formation by Non-glucuronidable Xenobiotics in Isolated Rat Hepatocytes

Rapid Stimulation of Free Glucuronate Formation by Non-glucuronidable Xenobiotics in Isolated Rat Hepatocytes

A Novel Mechanism for Regulating Hepatic Glycogen Synthesis Involving Serotonin and Cyclin-Dependent Kinase-5

Stimulation of glycogen synthesis and inactivation of phosphorylase in hepatocytes by serotonergic mechanisms, and counter-regulation by atypical antipsychotic drugs

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