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Role of Metabolism in Chemically Induced Nephrotoxicity
Published in Robin S. Goldstein, Mechanisms of Injury in Renal Disease and Toxicity, 2020
The ability of renal medullary tissue to oxidize certain drugs, even though this region of the kidney lacks the cytochrome P-450 monooxygenase system (Guder and Ross, 1984), suggested that another system was present that could bring about these reactions (Spry et al., 1986). Prostaglandin H synthase (PHS) is a heme-containing protein found predominantly in the interstitial and collecting duct cells of the renal medulla and in lesser amounts in the loop of Henle and medullary thick ascending limb. The protein is membrane bound, being associated with the endoplasmic reticulum and nuclear membranes. Two separate reactions are catalyzed, a fatty acid cyclooxygenase step and a prostaglandin hydroperoxidase step (Figure 5). The cyclooxygenase activity, which is specifically inhibited by aspirin and indomethacin, is responsible for the initial bis-dioxygenation of unsaturated fatty acid substrates, such as arachidonic acid. The product, a hydroperoxy cyclic endoperoxide, is then reduced by the hydroperoxidase activity to the hydroperoxy form. Methimazole and propylthiouracil are competitive inhibitors of the hydroperoxidase activity.
Pathways of Arachidonic Acid Metabolism
Published in Murray D. Mitchell, Eicosanoids in Reproduction, 2020
An outline of the enzymes involved in arachidonic acid metabolism is presented in Figure 1 and the major products of such metabolism are given in Figure 2. The formation of prostaglandins (cyclooxygenase pathway) begins with the action of prostaglandin endoperoxide synthase, synonymous with fatty acid cyclooxygenase, on arachidonic acid. There is an inherent peroxidase activity in the holoenzyme such that the PGG2 (15-hydroperoxy derivative) formed is rapidly converted to PGH2 (15-hydroxy derivative). Although these substances are short-lived intermediates, they do possess intrinsic biological activity. It is the formation of these endoperoxide intermediates that is inhibited by non-steroidal antiinflammatory agents. Thus, the biosynthesis of all prostaglandins and thromboxanes is inhibited by such drugs. The endoperoxide intermediates are metabolized further to prostaglandins by the actions of various isomerases. Evidence for a specific reductase to form PGF2α is still limited and it is likely that this conversion is often nonenzymatic. The enzymes of prostaglandin biosynthesis are located in the microsomal fraction of the cell with the exception of PGD2 (11-keto-) isomerase, which is a cytosolic enzyme.
Periodontal Disease and Osteomyelitis
Published in Wilson Harvey, Alan Bennett, Prostaglandins in Bone Resorption, 2020
This apparently minor role of TX is contested by Ohm et al.,23 who employed a combination of high performance liquid chromatography (HPLC) and RIA to detect a range of PGs in normal and diseased gingival tissue. They found the most significant endoperoxide metabolites were TXA2 (measured as TXB2) and PGI2 (measured as 6-keto-PGFja). TXB2 was increased 2.5-fold above normal in gingivitis and 21-fold in periodontitis; 6-keto-PGFja was increased 2.5- and 9.5-fold, respectively. PGE2 was the only other metabolite detected in any significant quantity, with concentrations 10 to 20% less than TXB2. They suggested that the relatively low values of PGE2 found in this study reflect the use of higher specificity antibodies than those used by Dewhirst et al.22
Metformin ameliorates ferroptosis in cardiac ischemia and reperfusion by reducing NOX4 expression via promoting AMPKα
Published in Pharmaceutical Biology, 2023
Zhenhua Wu, Yunpeng Bai, Yujuan Qi, Chao Chang, Yan Jiao, Yaobang Bai, Zhigang Guo
TRIzol reagent (Yanjin Biotechnology, Shanghai, China) was utilized to extract total RNA in rat cardiac tissues and H9c2 cells. The reverse transcription reaction was implemented by using the Reverse Transcription Kit (Invitrogen, Carlsbad, CA) with the following parameters: 70 °C, 5 min; 42 °C, 60 min; 70 °C, 15 min. Subsequently, PCR was carried out by applying the SYBR Green qPCR Reagent Kit (Biomars, Beijing, China) on the Bio-Rad CFX Connect Real-Time PCR Detection System (Bio-Rad, Hercules, CA). The procedure of PCR was 94 °C, 30 s; 56 °C, 30s; 72 °C, 30s, with 38 cycles. The primers were: prostagl and in-endoperoxide synthase 2 (PTGS2), forward 5′-GAGCACCATTCTCCTTGAAA-3′ and reverse 5′-ATTGAGGCAGTGTTGATGATT-3′. AMPKα, forward 5′-CGGAGCCTTGATGTGGTAGG-3′ and reverse 5′-TTCATCCAGCCTTCCATTCTT-3′. Actin, forward 5′-CATGTACGTTGCTATCCAGGC-3′ and reverse 5′-CTCCTTAATGTCACGCACGAT-3′. The relative expression of PTGS2 mRNA was calculated by the 2−ΔΔCT method and normalized to actin.
In vitro metabolism of HMTD and blood stability and toxicity of peroxide explosives (TATP and HMTD) in canines and humans
Published in Xenobiotica, 2021
Michelle D. Gonsalves, Lindsay McLennan, Angela L. Slitt, James L. Smith, Jimmie C. Oxley
Another possible explanation for rapid HMTD degradation is a Fenton-type reaction between the peroxide group and iron present in haemoglobin. Such interactions are responsible for the antimalarial properties of endoperoxide containing compounds, including HMTD (Vennerstrom 1989). Artemisinin and related synthetic derivatives are used today as malaria treatment. Studies have shown that endoperoxide group is vital for its activity. The mechanism of action is through the iron decomposing the peroxide group, which generates radical species that are toxic to the malaria parasite (Jefford 1997, Hindley et al.2002). The same reaction may be responsible for the apparent rapid degradation of HMTD observed in blood. As suspected with catalase, the methyl groups of TATP may sterically hinder any reaction with the iron in haemoglobin (Opsenica and Šolaja 2009).
The Relationship of COX-2 Gene Polymorphisms and Susceptibility to Kawasaki Disease in Chinese Population
Published in Immunological Investigations, 2019
Shentang Li, Ruting Shi, Lang Tian, Jia Chen, Xin Li, Lihua Huang, Zuocheng Yang
Cyclooxygenase-2 (COX-2) is an enzyme that in humans is encoded by the Prostaglandin-endoperoxide synthase 2 (PTGS2) gene. COX-2 converts arachidonic acid to prostaglandin endoperoxide H2 (PGH2). The synthesized PGH2 is subsequently converted to prostaglandins (PGD2, PGE2, PGF2α), prostacyclin (PGI2) or thromboxane A2 by tissue-specific isomerases. COX-2 is an inducible enzyme that is activated when the body suffers from extracellular stimuli, such as growth factors and proinflammatory cytokines. Among the prostaglandins, PGE2 can both strengthen vascular permeability and dilate the coronary arteries through four specific receptor subtypes (EP1, EP2, EP3 and EP4) in a complicated way, suppress T-cell receptor signals and help mitigate inflammation (Wiemer et al., 2011). PGE2 could induce the activation of beta(1)-integrin via the EP2 receptor in human coronary artery endothelial cells and this shows that the EP2 antagonist may modulate the inflammatory response of KD (Kajimoto et al., 2009). As a vasodilator, PGI2 plays a crucial part in regulating the homeostasis of the cardiovascular system and preventing atherosclerosis through inhibiting leukocyte adhesion, platelet aggregation and vascular smooth muscle cell proliferation (Kawabe et al., 2010).