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Renal Drug-Metabolizing Enzymes in Experimental Animals and Humans
Published in Robin S. Goldstein, Mechanisms of Injury in Renal Disease and Toxicity, 2020
Prostaglandin H synthase is a hemoprotein involved in the biosynthesis of prostaglandins and thromboxanes. The enzyme possesses two separable enzyme activities, fatty acid cyclooxygenase and prostaglandin hydroperoxidase (Ohki et al., 1979; Kulmacz and Lands, 1984), which have very different characteristics. Fatty acid cyclooxygenase requires specific substrates (ω-6-trienoic fatty acids), the activity can be selectively inhibited by aspirin, and it can use ferric or manganese haem. In contrast, prostaglandin hydroperoxidase can metabolize several different substrates, such as lipid hydroperoxides as well as hydrogen peroxide, there are no specific inhibitors of this enzyme, and it requires ferric haem (Spry et al., 1986). The substrates for prostaglandin H synthase include polyunsaturated fatty acids such as arachidonic acid (20:4) and eicosapentaenoic acid (20:5). Arachidonic acid is the major endogenous substrate which is converted to prostaglandin G2. Two atoms of molecular oxygen are inserted into the arachidonic acid to form a 15-hydroperoxy prostaglandin cyclic epoxide intermediate. Prostaglandin hydroperoxidase then catalyzes the cleavage of the 15-hydroperoxy group and acts as an electron donor, reducing prostaglandin G2 to H2, a 15-hydroxy cyclic endoperoxide. During this process prostaglandin hydroperoxide is reduced, resulting in cooxidation of a xenobiotic. Xenobiotic substrates include acetaminophen (Moldeus et al., 1982; Eling et al., 1983) and phenylbutazone, compounds implicated in renal papillary necrosis.
Metabolism and Toxicity of Antiprostaglandin Agents
Published in Sam Kacew, Drug Toxicity and Metabolism in Pediatrics, 1990
Cynthia R. Gelman, Barry H. Rumack
Aspirin has been shown to irreversibly inhibit the conversion of arachidonic acid to prostaglandin G2 by acetylation of the enzyme prostaglandin synthetase (cyclooxygenase). This inhibition results in inactivation of the prostaglandin pathway and prevention of synthesis of all prostaglandins.4 This knowledge lead to early trials evaluating the effectiveness of aspirin in the in utero treatment of patent ductus arteriosus5 as well as to inhibit premature labor.6 Aspirin taken at term has been reported to delay labor for 3 to 10 d.7 Other antiprostaglandin agents such as indomethacin have demonstrated better activity in the treatment of patent ductus arteriosus and are now exclusively used when pharmacologic therapy is indicated.
Role of Environmental Toxicants and Inflammation in Parkinson’s Disease
Published in Abhai Kumar, Debasis Bagchi, Antioxidants and Functional Foods for Neurodegenerative Disorders, 2021
Biddut Deb Nath, Dipti Debnath, Rokeya Pervin, Md. Akil Hossain
In the CNS, cyclooxygenase available as a COX-1, COX-2 and COX-3 isoforms, significantly incorporated in the synthesis of prostaglandins (PGs) from arachidonic acid (AA), is an essential glycoprotein of plasma membrane. The very first stage of PG biosynthetic pathway includes the transition of glycerophospholipid by phospholipase A2 into free AA, which is widespread in brain tissues and is upregulated through injury or infection.297 Afterwards, COX metabolizes AA into prostaglandin G2 (PGG2) and then prostaglandin H2 (PGH2), which is again converted into selected PG species by terminal synthases. AA is selectively metabolized to PGE2 by COX-2 (the most plentiful PG), while only small quantities of this prostanoid are produced by COX-1.298 Aside from these bioactive lipid mediators, during the COX-oriented peroxidative lowering of PGG2 to PGH2, significant quantities of ROS are produced. Inside the CNS, every three COX isozymes are expressed and spread irregularly in many distinct neural communities, where they facilitate a wide variety of disorders, activities, and health. In usual physiological states COX-2 participates in various responsive actions, involving gene expression, excitability of membrane, signaling and synaptic plasticity, REM sleep memory consolidation, and neurotransmission.297,299 Not unexpectedly, in addition to and as a consequence of acute inflammation connected with neurodegeneration, brain damage, or infection, COX-2 is susceptible to initiation by numerous inflammatory factors, several of which (such as ROS, cytokines) have been identified in the widespread induction of microglial cells. For illustration, LPS ingestion, or MPTP, DA toxin resulted in a significant rise in the expression of microglial COX-2.300
Ocular nonsteroidal inflammatory drugs: where do we stand today?
Published in Cutaneous and Ocular Toxicology, 2020
S. A. Kandarakis, P. Petrou, E. Papakonstantinou, D. Spiropoulos, A. Rapanou, I. Georgalas
Arachidonic acid (AA), a polyunsaturated fatty acid present in the phospholipids of cell membranes, represents the main wide range of biologically active eicosanoids and metabolites of these eicosanoids, signalling molecules with central role in immune responses, a subfamily of which is prostaglandins. Specifically, under various stimuli, free AA is released and subsequently converted via the COX pathway and lipoxygenase (LOX) enzyme catalysis to eicasonoids. In the COX pathway, the enzymes cyclooxygenase-1 and -2 (COX-1 and COX-2) metabolise AA to prostaglandin G2 and prostaglandin H2, which is then converted by various cell-specific isomerases and synthases, stimulating the biosynthesis of various PGs, prostacyclin and thromboxanes (TxA)6,7.
Clinical pharmacology of antiplatelet drugs
Published in Expert Review of Clinical Pharmacology, 2022
Georg Gelbenegger, Bernd Jilma
Membrane phospholipids are cleaved by phospholipase A2 (PLA2) to form arachidonic acid (AA) [6]. Arachidonic acid (AA) is then metabolized by cyclooxygenase (1 and 2), which results in the production of prostaglandin G2 (PGG2) and prostaglandin H2 (PGH2). Like TxA2, PGG2 and PGH2 themselves show vasoconstrictory effects. PGH2 is then further metabolized by specific synthases to produce prostaglandins D2, E2, F2, I2 and TxA2.
Protective effect of indomethacin on vanadium-induced adrenocortical and testicular damages in rat
Published in Toxicology Mechanisms and Methods, 2022
Rituparna Ghosh, Samudra Prosad Banik
The broad functions of NSAIDS are mediated through the prostaglandin and thromboxane pathways, which act on numerous biological and physiological processes, including reproduction. We wanted to explore the potential of one of such NSAIDs, indomethacin, in alleviation of vanadium induced toxicity to reproductive system. The synthesis of prostaglandin begins with the release of the precursor lipid, arachidonic acid, from the plasma membrane phospholipids by either phospholipase A2 or phospholipase C. The enzyme cyclooxygenase (COX) converts it to prostaglandin G2 and subsequently it is peroxidized to prostaglandin H2 by the same enzyme. Studies in recent years have demonstrated important roles for the COX enzyme in steroidogenesis and steroid hormone-regulated physiological functions in both human and animals (Wang et al. 2003). The present studies demonstrated that inhibition of COX activity by indomethacin dramatically increased steroid hormone production in rat testis exposed to vanadate. The increase in steroid output may be attributable to an increase in the activity of the steroidogenic enzymes Δ53β-HSD and 17β-HSD. The data suggested that enhanced testosterone production in COX inhibitor-supplemented rats showed a significant improvement in the growth of testes and accessory sex organs as these organs are highly androgen-dependent. However indomethacin alone could induce neither increase in steroidogenic enzyme activities nor a significant increase in testosterone production. The observations cumulatively suggested that the inhibitor itself did not have a direct stimulatory effect on steroid production, but rather, lowered the threshold of cAMP-stimulated steroidogenesis (Wang et al. 2003). Some studies have indicated the toxic effects associated with the use of NSAIDs like indomethacin, especially on male reproductive viability (Uzun et al. 2015; Bagoji et al. 2017). We carried out a dose-response curve for choosing the working concentration of indomethacin and found that concentrations in excess of 3 mg/kg of body weight decreased sperm count, sperm motility, serum gonadotropin and testosterone concentrations. Therefore, a single sub-toxic concentration of 1 mg/kg of body weight was selected for the studies.