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An Overview of Helminthiasis
Published in Venkatesan Jayaprakash, Daniele Castagnolo, Yusuf Özkay, Medicinal Chemistry of Neglected and Tropical Diseases, 2019
Leyla Yurttaș, Betül Kaya Çavușoğlu, Derya Osmaniye, Ulviye Acar Çevik
Levamisole (11) is a large-spectrum anthelmintic agent that is effective against ascardiasis and hookworm infections. It is a nicotinic receptor agonist and lead to spastic paralysis. The side effects of levamisole are mild and include nausea, headache, dizziness, skin rash and gastrointestinal disturbance. For the synthesis of levamisole, styrene oxide is initially reacted with ethanolamine followed by subsequent replacement of the hydroxyl groups using thionyl chloride to give 2-chloro-N-(2-chloroethyl)-2- phenylethan-1-amine. Acidic hydrolysis followed by reaction with thiourea led to a thiazolidine ring. The reaction of the latter molecule with thionyl chloride and alkaline treatment affords the racemic tetramizol, which is in turn separated into its dextro- and levo-isomers. Levamisole is the levo isomer of tetramizol (Akgün et al. 2013). The synthesis of Levamisole (11).
The Effects of Experimental Diabetes on the Cytochrome P450 System and Other Metabolic Pathways
Published in John H. McNeill, Experimental Models of Diabetes, 2018
Costas Ioannides, Peter R. Flatt, Christopher R. Barnett
The hydration of epoxides is catalyzed by epoxide hydrolases, which are localized in the microsomes and cytosolic fractions of the cell. When the microsomal activity was monitored using as substrate benzo(α)pyrene 4,5-oxide, activity was markedly enhanced in mice treated with streptozotocin.121 When the microsomal activity was monitored utilizing styrene oxide as the substrate a transient decline in activity was described in streptozotocin-treated rats.81,123 In contrast, when the cytosolic epoxide hydrolase activity was measured using trans-stilbene oxide, activity was increased following treatment of rats with either alloxan or streptozotocin and the effect was antagonized by insulin.122
Derivation and Modeling of Mechanistic Data for Use in Risk Assessment
Published in John C. Lipscomb, Edward V. Ohanian, Toxicokinetics and Risk Assessment, 2016
Epoxides and epoxide-forming chemicals, in addition to BD, include several of the highest production chemicals in the United States, e.g., ethylene/ethylene oxide, propylene/propylene oxide, styrene/styrene oxide, vinyl chloride, acrylonitrile, etc. A proposed pharmacodynamic approach to predict the carcinogenicity of this class of compounds involves the convergence of data on the in vitro mutagenicity of each epoxide (parent compound and metabolites) in putative target cells plus mathematical dosimetry models that predict the time- and dose-dependent in vivo concentrations of the mutagenic epoxides in target tissues of exposed animals. This approach is based on the hypothesis that tumor incidence resulting from exposure to epoxides and epoxide-forming chemicals is correlated with the cumulative number of mutations produced in a tissue at risk. Predictions of site-specific tumor dose–response might be feasible by relating model-based estimates of cumulative mutations in specific tissues to observed tumor incidence for several carcinogenic epoxide chemicals. If additional members of this family of chemicals act by a common mechanism, then the same relationship should hold for these agents as well, i.e., the carcinogenic activity of these agents should be represented by the same tumor incidence versus cumulative mutations curve for each tissue at risk.
Effects of concomitant exposure to styrene and intense noise on rats’ whole lung tissues. Biochemical and histopathological studies
Published in Drug and Chemical Toxicology, 2022
Mojtaba Haghighat, Abdolamir Allameh, Mohammad Fereidan, Ali Khavanin, Zahrasadat Ghasemi
It is now well established from a variety of studies that oxidative stress plays a key role in promoting lung tissue damage. Pathogenesis of ST is mediated by a family of cytochrome P450 (CYP) enzymes mostly located in the lungs (type II and Clara) and hepatic cells. Adverse effect of ST is usually attributed to oxidative stress and is based on this supposition that styrene oxide (SO), which is the main ST metabolite, is highly reactive. The abovementioned enzymatic system oxidizes ST to rodent carcinogen styrene-7, 8-oxide which ultimately forms DNA adducts (Boogaard et al.2000). Oxidative stress caused by an imbalance in the redox status of the body is directly associated with damage to DNA, lipids and proteins. Exposure to physical stressors like loud noise is also associated with oxidative stress including DNA damage (Lenzi et al.2003). The present study was designed to histopathologically and biochemically determine the effect of concomitant exposure to noise and ST on rat whole lung tissues.
A comprehensive review of cytochrome P450 2E1 for xenobiotic metabolism
Published in Drug Metabolism Reviews, 2019
Jingxuan Chen, Sibo Jiang, Jin Wang, Jwala Renukuntla, Suman Sirimulla, Jianjun Chen
Styrene, a monocyclic compound classified as a class 2B carcinogen, is oxidized to styrene oxide and 4-vinylphenol by CYP enzymes (CYPs). CYP2E1 plays a critical role in styrene conversion to the genotoxic metabolite, styrene oxide (Wenker et al. 2001). Styrene metabolism is involved in a two-site allosteric mechanism, and activity of styrene-bound free enzyme is approximately 10-fold less than that of the CYP2E1-styrene complex. Additionally, mixtures of styrene and other molecules (e.g. 4-methylpyrazole) were demonstrated to induce allosteric effects on binding and metabolism by CYP2E1. As a result, styrene metabolism is mitigated, and thus, the corresponding impacts on human health are assuaged (Hartman et al. 2012).
The common indoor air pollutant α-pinene is metabolised to a genotoxic metabolite α-pinene oxide
Published in Xenobiotica, 2022
Suramya Waidyanatha, Sherry R. Black, Kristine L. Witt, Timothy R. Fennell, Carol Swartz, Leslie Recio, Scott L. Watson, Purvi Patel, Reshan A. Fernando, Cynthia V. Rider
The metabolism of α-pinene to α-pinene oxide in rodents in vivo and in rodents and humans in vitro is a significant finding in our studies. Although not investigated here with α-pinene oxide, the reactivity of epoxides with critical macromolecules in the body has been well documented in the literature for a wide variety of xenobiotics (Lindstrom et al. 1998; Yeowell-O'Connell et al. 1998; Rappaport et al. 2002; Waidyanatha and Rappaport 2008; Waidyanatha et al. 2014). There are a number of examples of epoxides and/or epoxide-forming xenobiotics that are carcinogenic in humans and/or rodents, including ethylene oxide, acrylonitrile, butadiene, isoprene, benzene, and styrene (Melnick 2002). Many of these compounds have been shown to be genotoxic in a variety of metabolically competent test systems (Duverger et al. 1981; de Meester 1988; Dellarco et al. 1990; Watson et al. 2001; Albertini et al. 2010; French et al. 2015; Walker et al. 2020). Some, like 1,3-butadiene, require testing protocols that control for volatility (de Meester 1988), while others such as benzene, isoprene, and styrene are detected only after undergoing a complex process of metabolic transformation to yield the ultimate mutagenic metabolite(s), and this process can be influenced by species differences in P450 and other enzyme profiles, resulting in sex and species differences in exposure outcomes (Watson et al. 2001; Vodicka et al. 2006; French et al. 2015). Microsomal epoxide hydrolase rapidly detoxifies genotoxic epoxides, although shown to have a thresholding effect in vitro, in which low doses of styrene oxide were detoxified efficiently but additional exposures resulted in a significant increase in genotoxicity characterised by a linear dose-response curve (Oesch et al. 2000). In conclusion, the finding that α-pinene is metabolised to α-pinene oxide in both rat and human and that α-pinene oxide is mutagenic in the bacterial gene mutation assay suggest that further study of the carcinogenic potential of α-pinene is warranted.