Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01275 (glucagon)
 26,492 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Prostaglandin E2 (PGE2) can modulate the actions of a number of hormones in liver. PGE2 is rapidly metabolized in liver tissue, and thus alterations in the rate of PGE2 catabolism might exert a short-term influence on the concentration of PGE2 in liver. The present study examined the effects of inhibitors of oxidative metabolism on PGE2 catabolism and action in isolated rat hepatocytes. [3H]-PGE2 was metabolized to three major products by the hepatocyte system as assessed by reverse-phase high performance liquid chromatography. Metyrapone (5 mM), aminopyrine (5 mM), SKF-525A (20 microM) and alpha-naphthoflavone (20 microM) each inhibited the breakdown of [3H]-PGE2. The inhibition of oxidative metabolism by these compounds was not limited to action at cytochrome P-450, and metyrapone, aminopyrine and SKF-525A each was shown to inhibit [1-14C]-palmitate beta-oxidation in the hepatocyte system. To determine the contribution of beta-oxidation to the rapid catabolism of [3H]-PGE2, studies were performed using [1-14C]-PGE2 as substrate. Two major product peaks seen with [3H]-PGE2 as substrate lacked radioactivity when [1-14C]-PGE2 was the substrate, and thus these two products did not contain the 1-position carbon, consistent with their identity as beta-oxidation products. Furthermore, [1-14C]-PGE2 also yielded 14CO2 and a [14C]-PGE2 metabolite not seen with [3H]-PGE2. It was calculated that 60% of the rapid PGE2 inactivation in the hepatocyte system occurred via beta-oxidation. An additional, non-beta-oxidation, metyrapone-sensitive, pathway accounted for 26% of PGE2 disappearance. The effect of PGE2 to inhibit glucagon-stimulated glycogenolysis was potentiated when metyrapone was included in the incubation, consistent with increased survival of intact PGE2. In summary, PGE2 was rapidly inactivated by intact hepatocytes via oxidative metabolism, primarily beta-oxidation. Inhibition of prostaglandin catabolism can have short-term effects on PGE2 concentrations and result in potentiation of PGE2 effects on hepatic glucose metabolism.
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PMID:Inhibition of prostaglandin E2 catabolism and potentiation of hepatic prostaglandin E2 action in rat hepatocytes by inhibitors of oxidative metabolism. 316 76

(i) Hepatocytes isolated from adult rats were cultured for 2 to 3 weeks on collagen in a modified, serum-free Waymouth medium containing fatty acids and varying concentrations of glucocorticoid, insulin and glucagon. (ii) In the presence of all three hormones, it was possible to maintain the content of DNA, the activity of glucokinase, pyruvate kinase, hexokinase and lactate dehydrogenase at initial levels for 2 to 3 weeks. The activity of glucokinase and pyruvate kinase was affected by the concentration of insulin. (iii) The activity of alcohol dehydrogenase was stable for 3 days and declined to about 25% of the initial level after 2 weeks of culture, irrespective of the presence of hormones. (iv) Maintenance of albumin secretion was dependent on the presence of glucocorticoid, and glucocorticoid and insulin showed an additive or, at some time points, a synergistic effect on its secretion. (v) The content of cytochrome P-450 could be kept at 65% of the initial level, provided that a relatively high concentration of dexamethasone was present (10(-6) M). (vi) In the absence of hormones, urea synthesis was 70% of initial levels throughout the experimental period. With insulin and glucocorticoid present, a high concentration of glucagon (10(-8) M) was required to maintain the synthesis of urea at this level. (vii) It is concluded that hepatocyte cultures as described in the present study may be a useful, well-defined system for long-term metabolic, pharmacologic and toxicologic studies.
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PMID:Long-term culture of hepatocytes: effect of hormones on enzyme activities and metabolic capacity. 327 89

The content of cytochrome P-450 and the capacity for O-demethylation have been measured in cultures of hepatocytes from male and female rats for a period of 21 days. The effect of dexamethasone, insulin, glucagon, phenobarbital and hemin was investigated. In hepatocytes from female rats the content of cytochrome P-450 was unchanged after one day of culture. From day 1 to day 3 the content of cytochrome P-450 decreased by 65% and only the combined addition of dexamethasone, phenobarbital and hemin diminished the fall. After the initial fall, addition of 0.1 microM dexamethasone resulted in a stable value. Addition of 1 microM dexamethasone or 1 mM phenobarbital gave rise to an induction of cytochrome P-450 (285%). The high level of cytochrome P-450 was maintained for 3 weeks. In hepatocytes from male rats the content of cytochrome P-450 decreased by 40% after one day of culture. From day 1 to day 3 the content decreased by 45% and the decrease continued irrespective of the presence of hormones and/or phenobarbital. The O-demethylase activity in cultures of hepatocytes from female rats correlated to the cytochrome P-450 content independent of medium composition and age of the cultures, whereas no correlation was found in cultures from male rats. The present study demonstrates that hepatocytes from female rats in cultures retain O-demethylase activity for at least 3 weeks and that, with the experimental conditions used, the response to the hormones and inducers is different for hepatocytes from male and female rats.
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PMID:The content and activity of cytochrome P-450 in long-term culture of hepatocytes from male and female rats. 335 6

The continuous infusion of a low dose of glucagon (35 micrograms/kg/d, for 5 d) constitutes, in view of glucose-6-phosphatase and phosphoenolpyruvate carboxykinase activities, a reliable experimental model of hyperglucagonemia. By conjunction of monooxygenase assays and immunoquantitation of specific isozymes of cytochrome P-450, the actual inducing ability of glucagon has been shown and it might explain some of the modifications of the drug metabolizing system in diabetic mice. The isozymic pattern of cytochrome P-450 of liver microsomes from diabetic mice appears very different from that produced by classical inducers.
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PMID:The effect of different hyperglucagonemic states on monooxygenase activities and isozymic pattern of cytochrome P-450 in mouse. 402 53

Addition of glucose to cultured chick embryo hepatocytes caused a concentration-dependent impairment of phenobarbital-mediated induction of delta-aminolevulinate (ALA) synthase resembling the "glucose effect" observed in rodents in vivo. This glucose effect occurred in the complete absence of extrahepatic factors such as serum and hormones. Fructose, glycerol, and lactate mimicked the inhibitory glucose effect on ALA synthase induction, whereas 2-deoxyglucose and 3-O-methylglucose augmented the induction evoked by phenobarbital. 2-Deoxyglucose reversed the effect of glucose, glycerol, and lactate on ALA synthase induction suggesting that the glucose effect is mediated by free glucose or glucose 6-phosphate or a nonglycolytic metabolite of glucose 6-phosphate. The phenobarbital-mediated induction of cytochrome P-450 hemoprotein(s) and its monooxygenase function were concomitantly diminished by glucose. However, this inhibitory effect or glucose was reversible by the addition of exogenous heme or ALA suggesting that the primary target of the glucose effect is ALA synthase induction and not synthesis of apocytochrome P-450. Glucagon and dibutyryl cAMP enhanced the induction of ALA synthase and cytochrome P-450 by phenobarbital and partially counteracted the glucose effect on both enzymes suggesting that the glucose effect may be mediated by changes in cAMP levels. Although insulin did not alter induction of ALA synthase, it impaired induction of cytochrome P-450 even in the presence of glucagon and cAMP. These data may be relevant for the treatment with glucose and heme of patients with "inducible" hepatic porphyria.
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PMID:Induction of delta-aminolevulinate synthase and cytochrome P-450 hemoproteins in hepatocyte culture. Effect of glucose and hormones. 627 Jan 45

Metapyrone and eicosatetraynoic acid but not indomethacin are effective inhibitors of the secretory response of isolated rat pancreatic islets to arginine and glucose. Epoxyeicosatrienoic acids, products of the cytochrome P-450-NADPH dependent arachidonic acid epoxygenase activity, are potent and selective mediators for the in vitro release of either insulin or glucagon from preparations of isolated rat pancreatic islets.
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PMID:Epoxyeicosatrienoic acids stimulate glucagon and insulin release from isolated rat pancreatic islets. 641 Oct 91

Morphologically and functionally intact human hepatocytes were isolated from small liver biopsy samples weighing about 1-2 g by initial digestion with collagenase followed by repeated digestions with trypsin. The usual yield of hepatocytes was greater than 1 x 10(7) cells per g of liver sample and cell viability, as judged by dye exclusion test, was routinely over 90%. The isolated human hepatocytes showed intact morphology under scanning electron microscope. Formation of membrane protrusions upon phalloidin addition demonstrated that the actin in isolated hepatocytes was maintained with its structural integrity. The cultured human hepatocytes retained a variety of liver-specific functions which were similarly exhibited by rat hepatocytes isolated using the same procedure. The cultured human hepatocytes exhibited a specific cytochrome P-450 related enzyme activity, and active amino acid uptake that increased upon addition of hormones like glucagon and dexamethasone. Additionally, the cultured human hepatocytes synthesized DNA actively and, human serum albumin, and was found to be responsive to modulation by growth modulating hormones, cytokines and hepatotoxic agents. Based on the profile of activity described above, the presently established conditions for isolation and culturing of human hepatocytes demonstrate that functional liver cells can be obtained from small biopsied liver samples.
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PMID:Functional human hepatocytes: isolation from small liver biopsy samples and primary cultivation with liver-specific functions. 872 Jan 63

The CYP genes encode enzymes of the cytochrome P-450 superfamily. Cytochrome P-450 (CYP) enzymes are expressed mainly in the liver and are active in mono-oxygenation and hydroxylation of various xenobiotics, including drugs and alcohols, as well as that of endogenous compounds such as steroids, bile acids, prostaglandins, leukotrienes and biogenic amines. In the liver the CYP enzymes are constitutively expressed and commonly also induced by chemicals in a characteristic zonated pattern with high expression prevailing in the downstream perivenous region. In the present review we summarize recent studies, mainly based on rat liver, on the factors regulating this position-dependent expression and induction. Pituitary-dependent signals mediated by growth hormone and thyroid hormone seem to selectively down-regulate the upstream periportal expression of certain CYP forms. It is at present unknown to what extent other hormones that also affect total hepatic CYP activities, i.e. insulin, glucagon, glucocorticoids and gonadal hormones, act zone-specifically. The expression and induction of CYP enzymes in the perivenous region probably have important toxicological implications, since many CYP-activated chemicals cause cell injury primarily in this region of the liver.
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PMID:Zonation of hepatic cytochrome P-450 expression and regulation. 940 71

Our previous study on phase II detoxifying enzymes, showing a significant reduction of glutathione S-transferase-pi in chronic pancreatitis compared to the normal pancreas, indicated that xenobiotic-metabolizing enzymes are involved in the pathogenesis of pancreatic diseases. This study presents an overall look at the distribution of the phase I xenobiotic-metabolizing enzymes, which are responsible for the metabolism of many common environmental toxins and carcinogens, in the normal pancreas. Twenty-four normal pancreases from 7 donors and 17 early autopsy cases, as well as cultured human islet cells, were analyzed by immunohistochemistry, Western blot analysis, and/or reverse-transcription polymerase chain reaction (RT-PCR) for the expression of nine cytochrome P-450 mono-oxygenases (CYP) and the NADPH cytochrome P-450 oxidoreductase. Remarkable differences in the cellular distribution of these enzymes were found between the individuals and between different pancreatic cells within the same individual. Nondiabetics expressed more of the enzymes than diabetics, females more than males, younger more than older individuals, and organ donors (all young individuals) more than autopsy specimens. CYP 2B6 was expressed in all 7 donor pancreas, compared to 8 of 17 autopsy cases. Most of the enzymes were localized in islet cells and either were distributed in all islet cells or were restricted to, or expressed in a higher concentration in, glucagon and/or pancreatic polypeptide cells. Furthermore, a different cellular localization of the enzymes was found in some individuals (e.g., cytoplasmic vs. Golgi pattern of staining and a frequent nuclear localization of CYP 2E1 in females). Except for anti-CYP 1A2 and 3A4, RT-PCR and Western blot analyses validated the specificity of the antibodies. Our results show that islet cells play a major role in the detoxification process of the pancreas. The expression of individual enzymes and their distribution in acinar, ductal, and islet cells may determine individual susceptibility to pancreatic diseases.
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PMID:The pattern of xenobiotic-metabolizing enzymes in the human pancreas. 1239 72

Hepatic lipogenesis is the principal route to convert excess carbohydrates into fatty acids and is mainly regulated by two opposing hormones, insulin and glucagon. Although insulin stimulates hepatic lipogenesis, glucagon inhibits it. However, the mechanism by which glucagon suppresses lipogenesis remains poorly understood. In this study, we have observed that p38 mitogen-activated protein kinase plays an inhibitory role in hepatic lipogenesis. Levels of plasma triglyceride and triglyceride accumulation in the liver were both elevated when p38 activation was blocked. Expression levels of central lipogenic genes, including sterol regulatory element-binding protein-1 (SREBP-1), fatty acid synthase, hydroxy-3-methylglutaryl coenzyme A reductase, farnesyl pyrophosphate synthase, and cytochrome P-450-51, were decreased in liver by fasting and in primary hepatocytes by glucagon but increased by the inhibition of p38. In addition, we have shown that p38 can inhibit insulin-induced expression of key lipogenic genes in isolated hepatocytes. Our results in hepatoma cells demonstrate that p38 plays an inhibitory role in the activation of the SREBP-1c promoter. Finally, we have shown that transcription of the PGC-1beta gene, a key coactivator of SREBP-1c, was reduced in liver by fasting and in isolated hepatocytes by glucagon. This reduction was significantly reversed by the blockade of p38. Insulin-induced expression of the PGC-1beta gene was enhanced by the inhibition of p38 but suppressed by the activation of p38. Together, we have identified an inhibitory role for p38 in the transcription of central lipogenic genes, SREBPs, and PGC-1beta and hepatic lipogenesis.
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PMID:p38 mitogen-activated protein kinase plays an inhibitory role in hepatic lipogenesis. 1717 44


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