Regular ArticleCYP2E1-Dependent Bioactivation of 1,1-Dichloroethylene in Murine Lung: Formation of Reactive Intermediates and Glutathione Conjugates☆
Abstract
We investigated the cytochrome P450-dependent metabolism of 1,1-dichloroethylene (DCE) in murine lung microsomal incubations. The metabolites were identified as their glutathione conjugates or hydrolyzed products, analyzed by HPLC and quantified with [14C]DCE. We determined the relative quantities of DCE metabolites formed in lung microsomal incubations and compared them to those produced in liver. Furthermore, we used antibody inhibition experiments to investigate the CYP2E1-dependent metabolism of DCE in lung. Our results demonstrated that reactive intermediates were generated from DCE in the lung microsomal incubations. The DCE epoxide (12.6 ± 1.4 pmol/mg protein/min) was the major metabolite formed and was identified as two glutathione conjugates, 2-(S-glutathionyl) acetyl glutathione and 2-S-glutathionyl acetate. Lower levels of the acetal of 2,2-dichloroacetaldehyde (3.6 ± 0.25 pmol/mg protein/min) were detected. The ratio of acetal to DCE epoxide was higher in lung (0.30 ± 0.04) than in liver (0.12 ± 0.02). Preincubation of microsomes with a CYP2E1-inhibitory monoclonal antibody resulted in a maximum inhibition of 50% in the formation of both the acetal and the glutathione conjugates derived from the DCE epoxide. These data demonstrated that lung CYP2E1 metabolizes DCE to reactive intermediates of which the DCE epoxide is both the major metabolite formed and an efficient scavenger of glutathione, implicating it as an important toxic species mediating DCE-induced lung cytotoxicity.
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Selected Pneumotoxic Agents
2018, Comprehensive Toxicology: Third EditionThe toxicity of environmental chemicals, that is, nontherapeutic agents, to respiratory tissues is described in significant detail throughout this volume. In the vast majority of cases, these environmental toxicants are inhaled chemicals that interact with respiratory cells on a contact basis, after inhalation. There is, however, an ever-expanding repertoire of chemicals that produce selective or specific toxicity to cells within the respiratory system after systemic circulation throughout the biological system. Many of these chemicals are therapeutic agents such as bleomycin (BLM) or amiodarone (AM), and some are nontherapeutic chemicals such as 3-methylindole (3MI), aflatoxin B1 (AFB1), butylated hydroxytoluene (BHT), halogenated hydrocarbons, naphthalenes, paraquat (1,19-dimethyl-4,49-bipyridilium, PQ), the pyrrolizidine alkaloids (PZAs), and the substituted furans that are ingested and circulated systemically. This article deals with chemicals that are known to cause damage to respiratory tissues following exposure and the mechanisms of their toxicity, which is generally mediated by oxidative metabolism of the chemicals to reactive electrophiles by cytochrome P450 enzymes in cells of the respiratory tract. These compounds are generally toxic to nonciliated bronchiolar epithelial cells and alveolar epithelial cells of the gas exchange region although some agents are highly toxic to nasal epithelial or pulmonary endothelial cells. The purpose of this chapter is to provide chemical and biochemical insights into the generalized mechanisms of toxicity of certain circulating pneumotoxicants, through the enumeration and compilation of a few examples of well-documented, chemically induced lung damage.
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2010, Comprehensive Toxicology, Second EditionThe toxicity of environmental chemicals, that is, nontherapeutic agents, to respiratory tissues is described in significant detail throughout this volume. In the vast majority of cases, these environmental toxicants are inhaled chemicals that interact with respiratory cells on a contact basis, after inhalation. There is, however, an ever-expanding repertoire of chemicals that produce selective or specific toxicity to cells within the respiratory system after systemic circulation throughout the biological system. Many of these chemicals are therapeutic agents such as bleomycin (BLM) or amiodarone (AM) and some are nontherapeutic chemicals such as 3-methylindole (3MI), aflatoxin B1 (AFB1), butylated hydroxytoluene (BHT), halogenated hydrocarbons, naphthalenes, paraquat (1,19-dimethyl-4, 49-bipyridilium, PQ), the pyrrolizidine alkaloids (PZAs), and the substituted furans that are ingested and circulated systemically. This chapter deals with chemicals that are known to cause damage to respiratory tissues following exposure and the mechanisms of their toxicity, which is generally mediated by oxidative metabolism of the chemicals to reactive electrophiles by cytochrome P450 enzymes in cells of the respiratory tract. These compounds are generally toxic to nonciliated bronchiolar epithelial cells and alveolar epithelial cells of the gas exchange region, although some agents are highly toxic to nasal epithelial or pulmonary endothelial cells. The purpose of this chapter is to provide chemical and biochemical insights into the generalized mechanisms of toxicity of certain circulating pneumotoxicants, through the enumeration and compilation of a few examples of well-documented, chemically induced lung damage.
Dose-dependent transitions in mechanisms of toxicity: Case studies
2004, Toxicology and Applied PharmacologyExperience with dose response and mechanisms of toxicity has shown that multiple mechanisms may exist for a single agent along the continuum of the full dose–response curve. It is highly likely that critical, limiting steps in any given mechanistic pathway may become overwhelmed with increasing exposures, signaling the emergence of new modalities of toxic tissue injury at these higher doses. Therefore, dose-dependent transitions in principal mechanisms of toxicity may occur, and could have significant impact on the interpretation of reference data sets for risk assessment. To illustrate the existence of dose-dependent transitions in mechanisms of toxicity, a group of academic, government, and industry scientists, formed under the leadership of the ILSI Health and Environmental Sciences Institute (HESI), developed a series of case studies. These case studies included acetaminophen, butadiene, ethylene glycol, formaldehyde, manganese, methylene chloride, peroxisome proliferator-activated receptor (PPAR), progesterone/hydroxyflutamide, propylene oxide, vinyl acetate, vinyl chloride, vinylidene chloride, and zinc. The case studies formed the basis for technical discourse at two scientific workshops in 2003.
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Measurement of cytochrome P450 2E1 activity in rat tracheobronchial airways using high-performance liquid chromatography with electrochemical detection
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Selected Pneumotoxic Agents
2018, Comprehensive Toxicology, Third Edition: Volume 1-15
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This research is supported by Grant MT-11706 from the Medical Research Council of Canada (P.G.F.), Grant ES-06694 from the Southwest Environmental Health Sciences Center (J.B.U.), and Grant ES-04940 from the National Institute of Environmental Health Sciences (J.B.U.).
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