A study of the mechanism of quercetin oxygenation by 18O labelling. A comparison of the mechanism with that of haem degradation.
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ABSTRACT:
SUBMITTER: Brown SB
PROVIDER: S-EPMC1158469 | biostudies-other | 1982 Jul
REPOSITORIES: biostudies-other
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Project description:1. The pathway of haem breakdown in living rats was studied by using 18O in the oxygen that the animals consumed. By cannulation of the common bile duct and collection of bile, labelled bilirubin was isolated and its mass spectrum determined. One set of results was obtained for a rat to which haemoglobin had been intravenously administered and another set obtained for a rat that was not given exogenous haem. Isomerization of bilirubin IXalpha to the XIIIalpha and IIIalpha isomers did not occur to any significant extent. The 18O-labelling pattern obtained in the bilirubin was consistent with a Two-Molecule Mechanism, whereby the terminal lactam oxygen atoms of bilirubin are derived from different oxygen molecules. The consequences of this mechanism are discussed in terms of the possible intermediates of the catabolic pathway. 2. 18O-labelled bilirubin appeared in the bile in less than 10 min after exposure of the animals to labelled oxygen. This result suggests that all of the chemical transformations involving production of biliverdin, reduction to bilirubin and conjugation of the bilirubin are fast processes. 3. The quantitative recovery of label obtained in the experiments suggests that there is little or no exchange of newly synthesized bilirubin with existing bilirubin pools in the animal.
| S-EPMC1183896 | biostudies-other
Project description:The mechanism of bile-pigment formation from haem breakdown was studied by using 18O labelling of the molecular oxygen required for macrocyclic ring cleavage. For haem degradation by the spleen microsomal haem oxygenase system, mass spectrometry of the product bilirubin revealed that cleavage occurred by the Two-Molecule Mechanism, i.e. the terminal lactam oxygen atoms in bilirubin were derived from two different oxygen molecules. Similarly, degradation of myoglobin by coupled oxidation with ascorbate and oxygen proceeded via the Two-Molecule Mechanism. Cobalt and manganese complexes of protoporphyrin IX were not degraded by either the haem oxygenase system or the coupled oxidation system. This result suggests that the iron atom possesses unique properties in facilitating porphyrin breakdown.
| S-EPMC1185890 | biostudies-other
Project description:The degradation of haemoglobin to bilirubin in the rat was investigated by 18O labelling of the molecular oxygen consumed by the animal. The oxygen atoms incorporated into bilirubin were derived from two different oxygen molecules. Implications of this finding for the mechanism of haem catabolism in vivo are discussed; both verdohaem and a dioxygen-bridged compound appear to be excluded at intermediates.
| S-EPMC1165773 | biostudies-other
Project description:Coupled oxidation of octaethylhaemin and phenylhydrazine hydrochloride with 16,16O2 and 18,18O2 produced octaethyl[16O]verdohaemochrome and octaethyl[18O]-verdohaemochrome respectively. Reactions of these products with 16,16O2 in the presence of phenylhydrazine hydrochloride yielded octaethyl[16O, 16O]biliverdin and octaethyl[18O, 16O]biliverdin. The same reactions with 18,18O2 yielded octaethyl[16O, 18O]biliverdin and octaethyl[18O, 18O]biliverdin. Accordingly, the two oxygen atoms of biliverdin are incorporated from different O2 molecules in separate reactions, namely the formation of verdohaemochrome and the conversion of verdohaemochrome into biliverdin. These reactions account for a "two-molecule mechanism' of biliverdin formation from haem with verdohaemochrome participating as an intermediate product.
| S-EPMC1144775 | biostudies-other
Project description:The rate of haem degradation in aqueous pyridine shows a saturation dependence on O2 concentration. CO competitively inhibits the reaction. This is evidence for formation of an iron-O2 complex and is consistent with an intramolecular pathway for haem degradation.
| S-EPMC1186231 | biostudies-other
Project description:PurposeThere is general agreement that some dietary polyphenols block non-haem iron uptake, but the mechanisms by which they achieve this action are poorly understood. Since the polyphenol quercetin is ingested daily in significant amounts, we have investigated the effect of quercetin on duodenal non-haem iron absorption in vivo, as well as its effect on factors known to be involved in systemic iron metabolism.MethodsRats were subject to gastric gavage and systemic quercetin administration. Treatments were followed with uptake studies using radiolabeled iron, serum iron and transferrin saturation measurements, LC-MS/MS analysis of quercetin metabolites in serum, determination of tissue non-haem iron content and analysis of gene expression of iron-related proteins.ResultsBoth oral and intraperitoneal (IP) quercetin caused serum and tissue iron depletion by two means, first by increasing mucosal iron uptake and inhibiting iron efflux from duodenal mucosa, and second by decreasing levels of duodenal DMT1, Dcytb and FPN. Additionally, IP quercetin induced highly significant increased liver expression of hepcidin, a hormone known to inhibit intestinal iron uptake.ConclusionsOral quercetin significantly inhibited iron absorption, while IP quercetin significantly affected iron-related genes. These results could lead to development of new effective ways of preventing and treating iron deficiency anaemia, the most widespread nutritional disorder in the world.
| S-EPMC6437293 | biostudies-literature
Project description:The coupled oxidation of certain abnormal haemoglobins leads to different bile-pigment isomer distributions from that of normal haemoglobin. The isomer pattern may be correlated with the structure of the abnormal haemoglobin in the neighbourhood of the haem pocket. This is support for haem degradation by an intramolecular reaction.
| S-EPMC1185868 | biostudies-other
Project description:Quercetin is a natural flavonoid widely distributed in human diet and functional foods. Quercetin 3-O-?-glucuronide (Q3G) is present in wine and some medicinal plants. Quercetin and Q3G may be metabolized from each other in vivo. While quercetin has been the subject of many studies, the pharmacokinetic profiles of quercetin and Q3G (in animals) have not yet been compared. Herein, we prepared a column-based method for rapid isolation of Q3G from Nelumbo nucifera. Then, we developed an UHPLC-MS/MS method to compare the pharmacokinetics of quercetin and Q3G. Our results showed that the plasma concentration-time curves of quercetin and Q3G show two maxima (Tmax1???0.75?h, Tmax2???5?h). After oral administration of 100?mg/kg quercetin or 100?mg/kg Q3G in rats, predominantly Q3G was detected in plasma with AUC at 39529.2?±?6108.2?mg·h·L-1 or 24625.1?±?1563.8?mg·h·L-1, 18-fold higher than quercetin with AUC at 1583.9?±?583.3?mg·h·L-1 or 1394.6?±?868.1?mg·h·L-1, respectively. After intravenous injection of 10?mg/kg in rats, Q3G showed extensive tissue uptake in kidney (409.2?±?118.4?ng/g), liver (166.1?±?52.9?ng/g), heart (97.7?±?22.6?ng/g), and brain (5.8?±?1.2?ng/g). In conclusion, we have shown that Q3G is a major active component in plasma and tissue for oral administration of quercetin or Q3G.
| S-EPMC5075792 | biostudies-literature
Project description:Heme degradation through the action of heme oxygenase (HO) is unusual in that it utilizes heme as both a substrate and cofactor for its own degradation. HO catalyzes the oxygen-dependent degradation of heme to biliverdin with the release of CO and "free" iron. The characterization of HO enzymes from humans to bacteria reveals a similar overall structural fold that contributes to the unique reaction manifold. The heme oxygenases share a similar heme-dependent activation of O2 to the ferric hydroperoxide as that of the cytochrome P450s and peroxidases. However, whereas the P450s promote cleavage of the ferric hydroperoxide OO bond to the oxoferryl species the HOs stabilize the ferric hydroperoxide promoting hydroxylation at the heme edge. The alternate reaction pathway in HO is achieved through the conformational flexibility and extensive hydrogen bond network within the heme binding site priming the heme for hydroxylation. Until recently it was believed that all heme degrading enzymes converted heme to biliverdin and iron, with the release of carbon monoxide (CO). However, the recent discovery of the bacterial IsdG-like heme degrading proteins of Staphylococcus aureus, Bacillus anthracis and Mycobacterium tuberculosis has expanded the reaction manifold of heme oxidation. Characterization of the heme degradation products in the IsdG-like reaction suggests a mechanism distinct from the classical HOs. In the following review we will discuss the structure-function of the canonical HOs as it relates to the emerging alternate reaction manifold of the IsdG-like proteins.
| S-EPMC6476305 | biostudies-literature
Project description:Signaling pathways mediated by the mechanistic target of rapamycin (mTOR) play key roles in aging and age-related diseases. As a downstream protein of mTOR, transcription factor EB (TFEB) controls lysosome biogenesis and cellular trafficking, processes that are essential for the functions of phagocytic cells like the retinal pigment epithelium (RPE). In the current study, we show that a naturally occurring polyphenolic compound, quercetin, promoted TFEB nuclear translocation and enhanced its transcriptional activity in cultured RPE cells. Activated TFEB facilitated degradation of phagocytosed photoreceptor outer segments. Quercetin is a direct inhibitor of mTOR but did not influence the activity of Akt at the tested concentration range. Our data suggest that the dietary compound quercetin can have beneficial roles in neuronal tissues by improving the functions of the TFEB-lysosome axis and enhancing the capacities of cellular degradation and self-renewal.
| S-EPMC6230393 | biostudies-literature