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Functions of the Liver
Published in Peter Kam, Ian Power, Michael J. Cousins, Philip J. Siddal, Principles of Physiology for the Anaesthetist, 2020
Peter Kam, Ian Power, Michael J. Cousins, Philip J. Siddal
Haemoglobin is broken down in the reticuloendothelial system, particularly in the spleen. Haem is broken down by haem oxygenase and NADPH–cytochrome P-450 to biliverdin. Biliverdin is then converted to bilirubin by a reductase enzyme. About 85% of bilirubin is derived from the haem moiety of red cell haemoglobin; the remainder is derived from the breakdown of other haem-containing compounds. Bilirubin is bound to serum albumin and is transported to the liver. In the liver, the unbound bilirubin enters the hepatocyte, where rapid uptake occurs with two binding proteins being involved. The bilirubin is conjugated (via uridine diphosphate (UDP) glucuronyl transferase) with glucuronides, rendering it water soluble, and the conjugate is then secreted in the bile (Figure 37.6). In the gut, conjugated bilirubin is broken down by bacteria to form urobilinogen (which then enters enterohepatic circulation and is excreted in the urine), urobilin and stercobilin (which are excreted in the faeces).
Liver Diseases
Published in George Feuer, Felix A. de la Iglesia, Molecular Biochemistry of Human Disease, 2020
George Feuer, Felix A. de la Iglesia
In the mechanism of hemoglobin breakdown to bilirubin, several intermediates have been suggested (Figure 16). Hematin is considered to be a normal intermediary. In intravascular hemolysis such as hematin icterus, the production of hematin is increased without bilirubin elevation. Lack of hyperbilirubinemia suggests a shift in the normal metabolism to the accumulation of hematin. Animal experiments using labeled hemin are in agreement with the formation of this intermediate. The formation of choleglobin or verdohemoglobin, a green iron-containing protein complex, has also been proposed. By successive oxidation, the α-methene bridge is replaced by an ether bond. The next step leads to loss of iron and protein, and the biliverdin formed is reduced to bilirubin. The presence of biliverdin reductase and heme-α-methenyl oxygenase in the liver and kidney provides evidence for the existence of this pathway. Verdoglobinuria occurs in Pseudomonas septicemia, indicating that the bacterial toxin interferes with the complete metabolism of hemoglobin, resulting in the accumulation of verdoglobin.418,533
Therapeutic Gases for Neurological Disorders
Published in Sahab Uddin, Rashid Mamunur, Advances in Neuropharmacology, 2020
R. Rachana, Tanya Gupta, Saumya Yadav, Manisha Singh
When the upregulation of heme oxygenase 1 protein occurs, an increase in biliverdin also occurs. This biliverdin molecule is then reduced into the antioxidant and anti-nitrosative molecule, bilirubin by the activity of an enzyme biliverdin reductase. This is another mechanism which is also seen to have shown neuroprotective effects (Calabrese et al., 2007).
HMOX1 Promotes Ferroptosis Induced by Erastin in Lens Epithelial Cell through Modulates Fe2+ Production
Published in Current Eye Research, 2023
Shengjie Liao, Mi Huang, Yanli Liao, Chao Yuan
HMOX1 could metabolize heme into carbon monoxide, iron, and biliverdin. Biliverdin is subsequently converted to bilirubin by biliverdin reductase. To observe which by-products mediate the synergistic effect with erastin, CORM2, FeSO4, and bilirubin were added into HMOX1 knock-out cell medium with erastin. Figure 6(A) showed that CORM2 and bilirubin could not aggravate the cytotoxic effect of erastin in HMOX1 knock-out cells. Adding FeSO4 increase the sensitivity of the HLECs to erastin significantly. Then HMOX1 expression vector or empty vector were transiently transfected into HMOX1 knock-out cells, and cell viability and iron level were detected after 24 h treatment of erastin. Figure 6(B) showed that HMOX1 overexpression significantly decreased cell viability after erastin treatment. Indeed, total iron level increased when cells transfected with HMOX1 expression vector which could further increase after erastin treatment (Figure 6(C)). These data implied that iron liberated from heme by HMOX1 is a pivotal by-product that mediates the sensitivity elevation of erastin in HLECs.
The brain heme oxygenase/biliverdin reductase system as a target in drug research and development
Published in Expert Opinion on Therapeutic Targets, 2022
Biliverdin is not the final product of heme metabolism in humans because it is rapidly converted into BR in almost all cell types. Whether endogenous BV per se has biological effects or not is still a matter of debate, because it is sometimes hard to distinguish its own basal outcomes from those attributable to BR. As far as the nervous system is concerned, it has been shown that BV (2 µg/ml) counteracts inflammation and apoptosis in rat hippocampal neurons exposed to oxygen glucose deprivation/reoxygenation and reduce the extent of cerebral infarction and apoptosis in a rat model of middle cerebral artery occlusion/reperfusion injury [77]. Recently, Zou et al. have reported that BV (35 mg/kg intraperitoneally) modulates microRNA (miRNA) and mRNA to improve neurobehavior in rats with cerebral ischemia reperfusion damage [78]. In addition, it has been suggested that BV (10 µM and 50 µM) regulates the LPS-mediated expression of complement receptor 5a (C5aR) via the mTOR pathway in mouse macrophages [79]. Ultimately, BV (50 mg/kg intraperitoneally) protects against ischemia/reperfusion injury in cardiac, renal, and liver transplanted rats [80,81].
How could we forget immunometabolism in SARS-CoV2 infection or COVID-19?
Published in International Reviews of Immunology, 2021
The increased cytosolic phospholipase A2 (cPLA2) activity in PECs in severe COVID-19 patients may aggravate pulmonary inflammation as indicated (damaging membrane lipids, releasing arachidonic acid (AA), and promoting neutrophil infiltration) [110, 124]. The circulating glycerophospholipids, including phosphatidic acids (PAs), phosphatidylinositols (PIs), and phosphatidylcholines (PCs), along with their corresponding lysophospholipids, like lysophosphatidic acid (LPA), lysophosphatidylinositol (LPI), and lysophosphatidylcholine (LPC) increase due to the increase in PLA2 [110]. The increase in the plasma sphingolipid GM3 enriched exosomes in severe COVID-19 patients well correlates with the decrease in T cell count and CD4+ T cell count [110]. AA metabolism suppression occurs systemically in severe COVID-19 patients. VCAM-1 expression increases in COVID-19 patients and bilirubin (an inhibitor of VCAM-1) levels decrease. The biliverdin (oxidized bilirubin) level increases in circulation, indicating oxidative stress and ROS production [110]. The 5-hydroxy tryptophan (5-HT or oxitriptan) plasma levels also increase in COVID-19 patients indicating impaired serotonin production and altered behavior and mood in severe COVID-19 patients [110].