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

Arachidonic acid metabolites are involved in a wide spectrum of hepatobiliary physiologic functions and disease. Prostanoids alter hepatic bile flow. Prostaglandins with a C9 ketooxygen stimulate a bicarbonate-rich choleresis and those with a C9 hydroxyloxygen produce a chloride-rich choleresis. Prostaglandin F2 alpha stimulates the release of the potent choleretic glucagon and the stimulatory effect of prostaglandin F2 alpha on bile flow is inhibited by cyclooxygenase inhibitors, suggesting that prostaglandins play a role in the release of choleretic hormones as well as in their action. Prostanoids are involved in gallbladder contraction and water absorption. Prostaglandins produce gallbladder contraction in various species and cause gallbladder relaxation in other species. Prostaglandins also may be mediators of cholecystokinetic hormone action; however, cyclooxygenase inhibitors do not inhibit the effect of cholecystokinetic hormones in all species. Prostanoids alter the normal process of water absorption by gallbladder mucosa and induce net water secretion. The inflamed gallbladder secretes rather than absorbs fluid. The demonstration that prostaglandin E2 inhibits gallbladder fluid absorption has led to subsequent studies that demonstrated that the secretion of fluid into the inflamed gallbladder lumen may be mediated by prostanoids. In cholecystitis, the prostanoids may mediate the distention produced by mucosal fluid secretion and the contraction of the diseased gallbladder. The inflammatory changes produced in various experimental models of cholecystitis can be prevented by cyclooxygenase inhibitors. Cyclooxygenase inhibitors decrease gallbladder prostaglandin formation and are effective in producing relief of the symptoms of gallbladder disease. In experimental cholesterol gallstone formation, prostaglandins are involved in the production of mucin, which acts as a nidus for stone formation, and cyclooxygenase inhibitors prevent the formation of experimental cholesterol gallstones. Prostaglandins have been shown to be cytoprotective in various types of experimental hepatic injury and leukotrienes have been shown to be injurious to hepatocytes and biliary tract tissues. Specific prostanoids and lipoxygenase inhibitors may be valuable in treating patients with various acute hepatic inflammatory disease processes. Continued evaluation of the role of arachidonic acid metabolites in hepatobiliary physiology and disease may lead to important new therapeutic modalities.
 ...
PMID:Arachidonic acid metabolites in hepatobiliary physiology and disease. 266 54

Some metabolic effects of prostaglandins have been related to their alteration of adenosine-3',5'-monophosphate (cyclic AMP) metabolism in different tissues. Prostaglandins E1 and E2 stimulate liver adenylate cyclase in vitro, but conflicting reports have been made about metabolic changes caused by E prostaglandins in hepatic tissue. We have attempted to resolve these issues by comparing the effects of PGE1 with those of glucagon using broken-cell homogenates, intact hepatocytes, liver slices and perfused liver. Prostaglandin E1 (PGE1) increased cyclic AMP in liver slices and in perfused liver without increasing glycogenolysis, but PGE1 had no discernible effect on carbohydrate or cyclic AMP metabolism in isolated hepatocytes. Glucagon caused predictable increases in cyclic AMP and glycogenolysis using hepatocytes, liver slices or perfused liver. These data can be explained by the absence of PGE effects on cyclic AMP metabolism in hepatocytes. The concentration of E prostaglandins (PGEs) increased 1.75-fold during incubations (37 degrees C) of hepatocyte suspensions, but cyclic AMP remained constant. Addition of exogenous arachidonate and indomethacin to cell suspensions increased and decreased PGEs, respectively, but cyclic AMP and glycogen metabolism were unchanged. Arachidonate and indomethacin likewise did not alter glucagon-stimulated glycogenolysis or cyclic AMP biosynthesis. The production of E prostaglandins and cyclic AMP appears to be unrelated in hepatocytes.
 ...
PMID:Dissociation of E prostaglandin effects on liver glycogenolysis and cyclic AMP levels. 631 5

Oxytocin (OT) and vasopressin (AVP) stimulate insulin and glucagon release from the pancreas, and evoke insulin secretion from the rat insulinoma cell line, RINm5F. To determine which AVP/OT receptor subtype is expressed in RINm5F cells, we used PCR with degenerate primers to two transmembrane domains of the AVP (V1a, V1b (or V3), V2) and OT receptors (OTRs). The single PCR fragment identified was used to obtain a full length cDNA from a RINm5F cDNA library. Comparison of the deduced amino acid sequence of this clone with uterine OTR sequences from several species (human, sheep, bovine) and to the pig kidney epithelial cell (LLC-PK1) OTR reveals a very high degree of homology. After the RIN cell OTR cDNA was stably transfected into CHO cells (CHO-OTR), the cell membranes bound iodinated oxytocin antagonist with an apparent Kd comparable to that of RIN cell membranes and those from other OT target cells. Comparison of the ligand specificities of CHO-OTR and RIN cells membranes showed that the relative Ki values of a series of OT analogues were approximately equivalent in both preparations. The rank order of apparent Ki values also corresponded to published values for the rat myometrium, where OT elicits intracellular calcium transients, and increases inositol phosphate production. In uterin endometrium and amnion cells, OT stimulates prostaglandin release. Stimulation of CHO-OTR cells with OT caused an increase in cytosolic calcium concentration originating from both intracellular and extracellular sources, and a dose-dependent increase in inositol phosphate levels. Arachidonic acid release and PGE2 synthesis were also stimulated by OT. These findings (amino acid sequence homology, binding specificity, and signal transduction/second messenger production) suggest that OTRs from RINm5F cells are indistinguishable from OTRs that have been described in other tissues. The expression of OTR in pancreatic cells implies that OT plays a role in pancreatic function.
 ...
PMID:Molecular cloning and functional characterization of the oxytocin receptor from a rat pancreatic cell line (RINm5F). 900 55

Arachidonic acid (AA) can undergo monooxygenation or epoxidation by enzymes in the cytochrome P450 (CYP) family in the brain, kidney, lung, vasculature, and the liver. CYP-AA metabolites, 19- and 20-hydroxyeicosatetraenoic acids (HETEs), epoxyeicosatrienoic acids (EETs) and diHETEs have different biological properties based on sites of production and can be stored in tissue lipids and released in response to hormonal stimuli. 20-HETE is a vasoconstrictor, causing blockade of Ca(++)-activated K(+) (KCa) channels. Inhibition of the formation of nitric oxide (NO) by 20-HETE mediates most of the cGMP-independent component of the vasodilator response to NO. 20-HETE elicits a potent dilator response in human and rabbit pulmonary vascular and bronchiole rings that is dependent on an intact endothelium and COX. 20-HETE is also a vascular oxygen sensor, inhibits Na(+)/K(+)-ATPase activity, is an endogenous inhibitor of the Na(+)-K(+)-2Cl(-)cotransporter, mediates the mitogenic actions of vasoactive agents and growth factors in many tissues and plays a significant role in angiogenesis. EETs, produced by the vascular endothelium, are potent dilators. EETs hyperpolarize VSM cells by activating KCa channels. Several investigators have proposed that one or more EETs may serve as endothelial-derived hyperpolarizing factors (EDHF). EETs constrict human and rabbit bronchioles, are potent mediators of insulin and glucagon release in isolated rat pancreatic islets, and have anti-inflammatory activity. Compared with other organs, the liver has the highest total CYP content and contains the highest levels of individual CYP enzymes involved in the metabolism of fatty acids. In humans, 50-75% of CYP-dependent AA metabolites formed by liver microsomes are omega/omega-OH-AA, mainly w-OH-AA, i.e. 20HETE, and 13-28% are EETs. Very little information is available on the role of 19- and 20-HETE and EETs in liver function. EETs are involved in vasopressin-induced glycogenolysis, probably via the activation of phosphorylase. In the portal vein, inhibition of EETs exerts profound effects on a variety of K-channel activities in smooth muscles of this vessel. 20-HETE is a weak, COX-dependent, vasoconstrictor of the portal circulation. EETs, particularly 11,12-EET, cause vasoconstriction of the porto-sinusoidal circulation. Increased synthesis of EETs in portal vessels and/or sinusoids or increased levels in blood from the meseneric circulation may participate in the pathophysiology of portal hypertension of cirrhosis. CYP-dependent AA metabolites are involved in the pathophysiology of portal hypertension, not only by increasing resistance in the porto-sinusoidal circulation, but also by increasing portal inflow through mesenteric vasodilatation. In patients with cirrhosis, urinary 20-HETE is several-fold higher than PGs and TxB2, whereas in normal subjects, 20-HETE and PGs are excreted at similar rates. Thus, 20-HETE is probably produced in increased amounts in the preglomerular microcirculation accounting for the functional decrease of flow and increase in sodium reabsorption. In conclusion, CYP-AA metabolites represent a group of compounds that participate in the regulation of liver metabolic activity and hemodynamics. They appear to be deeply involved in abnormalities related to liver diseases, particularly cirrhosis, and play a key role in the pathophysiology of portal hypertension and renal failure.
 ...
PMID:Role of cytochrome P450-dependent arachidonic acid metabolites in liver physiology and pathophysiology. 1462 96