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Phagocytosis By Human Neutrophils
Published in Hans H. Gadebusch, Phagocytes and Cellular Immunity, 2020
Recently, attention has been focused on the production of highly reactive intermediates of oxygen metabolism. Babior et al.196,197 have demonstrated that phagocytizing neutrophils generate superoxide anions (02”) employing an assay that relies upon the ability of 02” to reduce cytochrome c+3. The assay must be run in the presence and absence of superoxide dismutase (SOD) to ensure that the reduction observed is, indeed, mediated by 02". Only that amount of reduction that can be inhibited by SOD can be attributed to superoxide. This assay has the same limitation as that previously described for H2O2 in that only superoxide anion that escapes from the cell into the medium is detectable. Because of its highly reactive nature, this undoubtedly represents only a fraction of the 02_ actually formed.
Renal, Cardiovascular, and Pulmonary Functions of Dopamine
Published in Nira Ben-Jonathan, Dopamine, 2020
Oxidative stress causes an imbalance between the production of reactive oxygen species (ROS) and the system’s ability to detoxify reactive intermediates or repair the resulting damage [9,19]. ROS are generated by enzymes such as NADPH oxidases, which are membrane-bound enzyme complexes facing the extracellular space. The enzymes catalyze the production of a superoxide free radical by transferring one electron from NADPH to oxygen: . During the process, O2 is transported from the extracellular space to the cell interior and an H+ is exported. Superoxide is the precursor of most reactive oxygen species. Dismutation of a superoxide by superoxide dismutase (SOD) enzymes, produces hydrogen peroxide . Hydrogen peroxide in turn may be partially reduced to hydroxyl radical (•OH) or fully reduced to water: . Other reactions can convert hydrogen peroxide to hypochlorous acid (HClO), which is very reactive and can cause significant oxidative damage. Oxidative stress, through the overproduction of peroxides and free radicals, can cause apoptosis and damage various components of the cell, including proteins, lipids, and DNA. Positive effects of ROS include the induction of host defense genes and the mobilization of ion transport systems.
Benzene Metabolism (Toxicokinetics and the Molecular Aspects of Benzene Toxicity)
Published in Muzaffer Aksoy, Benzene Carcinogenicity, 2017
Keith R. Cooper, Robert Snyder
The study of biological reactive intermediates has yielded many observations which indicate that metabolic activation can yield chemically reactive species which react nonenzymatically with cellular macromolecules to modify their activity and thereby produce toxicity. Symposiums on biological reactive intermediates have permitted the collection of considerable data on these reactions and their effects.129,130 Covalent binding of reactive metabolites to DNA is thought to be a potential cause of cell pathology or carcinogenesis. We have focused on the covalent binding of benzene metabolites to DNA because benzene inhibits DNA synthesis,95 benzene binds to DNA liver131 and bone marrow,126 and because the target organ, i.e., the bone marrow, has as its main concern the rapid proliferation of many cell types. Clearly, binding to DNA could have a profound effect on rapidly dividing cells.
Andrographis paniculata mitigates first-line anti-tubercular drugs-induced nephrotoxicity in Wistar rats
Published in Biomarkers, 2022
Varsha Sharma, Radhika Sharma, Vijay Lakshmi Sharma
Drugs as xenobiotics are liable for a wide range of adverse effects besides their curative potential on the human body against various diseases. Disposition of orally administrated drug involves absorption in the blood and gastrointestinal tract, and its biotransformation in the liver that is primarily performed by xenobiotic enzymes system. In drug metabolism, enzymes of phase I and phase II systems are actively involved in the metabolic activation of drugs and detoxification, respectively. By the action of phase I enzymes, xenobiotics are firstly converted into active intermediates subsequently with the aid of phase II enzymes these intermediates are conjugated with endogenous cofactors and excreted out with urine. RMs are not only acting as inducers or inhibitors for the enzymes involved in drug metabolism but also one of the factors for the production of ROS. Different reactive forms, such as superoxide anion, hydrogen peroxide, and hydroxyl radical are normally and continuously formed inside the cell during the normal course of aerobic metabolism, detoxification, chemical signalling, and immune functioning. ROS-mediated oxidative stress is devastated by the antioxidant defense system of our body that includes glutathione, catalase, superoxide dismutase, and glutathione-S-transferase. Reactive intermediates of drug metabolism and collapse in the antioxidant defense system could influence the composition of lipids, proteins, and nucleic acid of the cell (Valko et al. 2006).
Caffeic acid phenethyl ester, a propolis polyphenolic, attenuates potentially cadmium-induced testicular dysfunction in mice
Published in Toxin Reviews, 2020
Pin Gong, Xuyang Xiao, Lan Wang, Wenjuan Yang, Xiangna Chang
Once absorbed, Cd rapidly concentrates in various tissues and cause acute or chronic Cd poisoning that is associated with a variety of severe damage, particularly to the testis (Ognjanovi et al.2010). Based on a number of recent reports, it is evident that the testis is extremely sensitive to Cd toxicity (Erboga et al.2016). Earlier investigation (Mohajeri et al.2017) suggests that Cd-induced testicular toxicity has been associated with the excessive production of reactive oxygen species (ROS). Oxidation by ROS has been reported to decrease sperm motility in association with male infertility (Riaz et al.2015). In addition, these reactive intermediates interact with the cellular macromolecules and result in oxidative deterioration of lipids, membrane protein and DNA (Waisberg et al.2003, Mollaoglu et al.2006). Besides, Cd toxicity is reported to be associated with modification in thiol-containing proteins, inhibition of energy metabolism, membrane damage and altered gene expression (Wilmink et al.1999, Satarug et al.2003, Murugavel and Pari 2007, Larregle et al.2008). However, the underlying mechanism has not been well characterized yet (Ilhan et al.1999).
Phase I and phase II metabolism simulation of antitumor-active 2-hydroxyacridinone with electrochemistry coupled on-line with mass spectrometry
Published in Xenobiotica, 2019
Agnieszka Potęga, Dorota Garwolińska, Anna M. Nowicka, Michał Fau, Agata Kot-Wasik, Zofia Mazerska
Solid understanding of the metabolic pathways and the biotransformation mechanisms of new drug candidates is a crucial point in the drug discovery and development processes. Overall, it allows to elucidate the metabolic activation as well as the deactivation routes of new biologically active compounds, especially with respect to their possible toxicity (Park et al., 2011). The identification of metabolites helps to eliminate the inappropriate candidates at an early stage, before the more expensive development phases will be performed (Bussy & Boujtita, 2014). Particularly, it is very important that the formation of chemically reactive intermediates is checked (Baillie et al., 2002), because an increasing number of reports indicate that they are responsible for the majority of rapid and unexpected drug toxic effects (Kalgutkar & Soglia, 2005; Orhan & Vermeulen, 2011; Srivastava et al., 2010). The relationship between drug metabolism and adverse drug reactions was first demonstrated with the analgesic agent acetaminophen (Jollow et al., 1973; Larson, 2007). Reactive intermediates generated usually via cytochrome P450 (P450)-catalyzed oxidative reactions, have the potential for covalent binding to cellular nucleophiles such as purine and pyrimidine bases of DNA or thiols of proteins and form stable adducts. Adduct formation may alter biological functions of these biomolecules what ultimately leads to a toxic response (Brandon et al., 2003).