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Diabetes Mellitus, Obesity, Lipoprotein Disorders and other Metabolic Diseases
Published in John S. Axford, Chris A. O'Callaghan, Medicine for Finals and Beyond, 2023
There is skin photosensitivity in childhood. Accumulation of protoporphyrin may cause chronic liver disease leading to liver failure and death. Protoporphyrin levels are increased in bone marrow, circulating erythrocytes, plasma, bile and faeces.
The Ferrochelatase Deficiency (Fechm1Pas) Mutation, Chromosome 18
Published in John P. Sundberg, Handbook of Mouse Mutations with Skin and Hair Abnormalities, 2020
Plasma bilirubin (mainly, conjugated bilirubin) is markedly increased (50-fold) in homozygotes. Protoporphyrin levels are also considerably elevated in erythrocytes (25-fold), plasma (20- to 200-fold), liver (1000-fold), and stool (10-fold). Serum alkaline phosphatase and transaminases are consistently increased as a consequence of chronic liver damage.
Porphyric Red Cells
Published in Ronald L. Nagel, Genetically Abnormal Red Cells, 2019
Within the erythrocyte, protoporphyrin is bound to hemoglobin. The binding place of protoporphyrin on hemoglobin has been a matter of controversy. Lamola et al.189 favor a view where protoporphyrin is not bound in the heme pocket, but on some other place on the hemoglobin molecule. Their conclusion is based on the different fluorescence spectra of protoporphyrin-globin, where protoporphyrin is known to be in the heme pocket, and protoporphyrin-hemoglobin from patients with erythropoietic protoporphyria.189 This conclusion was refuted by van Steveninck et al.190 who showed that the difference in fluorescence maxima could be explained by an inner filter effect of hemoglobin. The same group also demonstrated that protoporphyrin-hemoglobin from EPP patients had different properties from protoporphyrin mixed with hemoglobin. In contrast, after mixing protoporphyrin with hemiglobin in which protoporphyrin can be exchanged for hemin, a protoporphyrin-hem-iglobin complex is formed which has the same physiochemical properties as protoporphyrin-hemiglobin from patients with erythropoietic protoporphyria.191 They therefore concluded that free protoporphyrin in erythrocytes from patients with erythropoietic protoporphyria was bound on the heme binding places.191
Antiperspirant effects and mechanism investigation of Mulisan decoction in rats based on plasma metabolomics
Published in Pharmaceutical Biology, 2022
Shan-Peng Ma, Wei-Ping Ma, Shi-Ning Yin, Xiang-Yue Chen, Xiao-Qing Ma, Bao-Hong Wei, Jing-Guang Lu, Hong-Bing Liu
Protoporphyrin IX is a critical metabolite in porphyrin metabolism, whose level is vital to the health of the body. It can promote cell tissue respiration and improve protein and glucose metabolism (Zhu et al. 2020). Protoporphyrin IX is the intermediate product in the process of haemachrome and a precursor of haemoglobin (Immenschuh et al. 2017). Abnormal porphyrin metabolism can lead to the accumulation of porphyrins in vivo, and then damage the function of mitochondria. Mitochondria can convert food and oxygen into adenosine triphosphate (ATP) through the respiration effect to meet the large energy needs of the body (Paes et al. 2020). In this study, MLS could significantly increase the level of protoporphyrin IX in RP rats, indicating that MLS could improve porphyrin metabolism and reduce porphyrin accumulation in RP rats to restore cell mitochondrial function and promote energy production. This is beneficial to improve sweating symptoms in RP rats.
The structure of CLEC-2: mechanisms of dimerization and higher-order clustering
Published in Platelets, 2021
Eleyna M Martin, Malou Zuidscherwoude, Luis a Morán, Ying Di, Angel García, Steve P Watson
Bourne et al [5]. recently identified hemin as an endogenous ligand for CLEC-2. Hemin, the oxidized form of heme, is a protoporphyrin IX containing an Fe3+ ion with an associated chloride ligand, structure displayed in Figure 5. Hemin is found in the bloodstream during hemolytic conditions during which prothrombotic and proinflammatory responses are induced. The work of Bourne et al [5]. demonstrated that hemin is able to activate human and mouse platelets through direct binding to CLEC-2. They revealed that hemin at low micromolar concentrations induced rapid aggregation of human platelets in association with phosphorylation of Syk and PLCγ2, and that aggregation was blocked by inhibitors of Syk, SFKs and Btk consistent with an ITAM receptor-based pathway. SPR was used to confirm direct binding to CLEC-2 and determine the affinity of hemin to dimeric Fc-fusion human and mouse CLEC-2 to be in the order of 200 nM. Platelet aggregation induced by hemin was not blocked by anti-human CLEC-2 monoclonal antibody AYP1 suggesting that hemin binds to a site distinct from rhodocytin and podoplanin, which compete with AYP1 for CLEC-2 binding (discussed further below)[17].
Adverse pharmacokinetic interactions between illicit substances and clinical drugs
Published in Drug Metabolism Reviews, 2020
Kodye L. Abbott, Patrick C. Flannery, Kristina S. Gill, Dawn M. Boothe, Muralikrishnan Dhanasekaran, Sridhar Mani, Satyanarayana R. Pondugula
Adverse pharmacokinetic interactions may also occur due to dysregulation of endobiotic homeostasis, leading to an excessive accumulation of endobiotics or endobiotic byproducts, resulting in toxicity or tissue injury (Figure 4). For example, co-therapy of isoniazid and rifampicin has been reported to cause dysregulation of porphyrin homeostasis, resulting in pronounced accumulation of protoporphyrin IX (PPIX), an intermediary in the synthesis of heme (Li et al. 2013). It is important to note that both isoniazid and rifampicin activate PXR and induce excessive accumulation of PPIX in a PXR-dependent manner. In abundance, PPIX acts as a hepatotoxin and causes liver injury in PXR-humanized mice (Li et al. 2013). The co-therapy of isoniazid and rifampicin resulted in enhanced hepatotoxicity compared with isoniazid or rifampicin alone (Li et al. 2013). Mechanistically, aminolevulinic acid synthase1 (ALAS1), which is the rate limiting enzyme in porphyrin biosynthesis in the liver, is upregulated by both isoniazid and rifampicin via PXR (Fraser et al. 2003). Ferrochelatase (FECH), which catalyzes the insertion of ferrous ions into PPIX to form heme, is downregulated by isoniazid most likely via PXR (Li et al. 2013).