A search for cellular and molecular mechanisms involved in depleted uranium (DU) toxicity
Identifieur interne : 001D84 ( Main/Exploration ); précédent : 001D83; suivant : 001D85A search for cellular and molecular mechanisms involved in depleted uranium (DU) toxicity
Auteurs : Jalal Pourahmad [Iran, Canada] ; Monireh Ghashang [Iran] ; Hossein Ali Ettehadi [Iran] ; Ruhollah Ghalandari [Iran]Source :
- Environmental Toxicology [ 1520-4081 ] ; 2006-08.
English descriptors
- Teeft :
- Acridine, Butylated, Butylated hydroxyanisole, Butylated hydroxytoluene, Control hepatocytes, Cytotoxicity, Dimethyl sulfoxide, Diphenyliodonium chloride, Emission wavelengths, Environmental toxicology, Glutathione, Hepatocyte, Hepatocyte toxicity, Hepatocytes, Inhibitor, Intracellular, Lipid, Lipid peroxidation, Lung cancer, Lysosomal, Membrane, Mitochondrial, Mitochondrial membrane, Molecular mechanisms, Oxygen uptake, Peroxidation, Pourahmad, Reactive, Reduction inhibitor, Reductive, Separate experiments, Tbars, Toxicity, Toxicology, Uorescence, Uorescence spectrophotometer, Uranyl, Uranyl acetate.
Abstract
Addition of U(VI) (uranyl acetate) to isolated rat hepatocytes results in rapid glutathione oxidation, reactive oxygen species (ROS) formation, lipid peroxidation, decreased mitochondrial membrane potential, and lysosomal membrane rupture before hepatocyte lysis occurred. Cytotoxicity was prevented by ROS scavengers, antioxidants, and glutamine (ATP generator). Hepatocyte dichlorofluorescein oxidation was inhibited by mannitol (a hydroxyl radical scavenger) or butylated hydroxyanisole and butylated hydroxytoluene (antioxidants). Glutathione depleted hepatocytes were resistant to U(VI) toxicity and much less dichlorofluorescein oxidation occurred. Reduction of U(VI) by glutathione or cysteine in vitro was also accompanied by oxygen uptake and was inhibited by Ca(II) (a U(IV) or U(VI) reduction inhibitor). U(VI)‐induced cytotoxicity and ROS formation was also inhibited by Ca(II), which suggests that U(IV) and U(IV) GSH mediate ROS formation in isolated hepatocytes. The U(VI) reductive mechanism required for toxicity has not been investigated. Cytotoxicity was also prevented by cytochrome P450 inhibitors, particularly CYP 2E1 inhibitors, but not inhibitors of DT diaphorase or glutathione reductase. This suggests that P450 reductase and reduced cytochrome P450 contributes to U(VI) reduction to U(IV). In conclusion, U(VI) cytotoxicity is associated with mitochondrial/lysosomal toxicity by the reduced biological metabolites and ROS. © 2006 Wiley Periodicals, Inc. Environ Toxicol 21: 349–354, 2006.
Url:
DOI: 10.1002/tox.20196
Affiliations:
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last="Pourahmad">Jalal Pourahmad</name><affiliation wicri:level="1"><country xml:lang="fr">Iran</country><wicri:regionArea>Faculty of Pharmacy and Pharmaceutical Research Center, Shaheed Beheshti University of Medical Sciences, Tehran, P.O.Box 14155‐6153</wicri:regionArea><wicri:noRegion>P.O.Box 14155‐6153</wicri:noRegion></affiliation><affiliation wicri:level="1"><country wicri:rule="url">Canada</country></affiliation><affiliation wicri:level="1"><country xml:lang="fr">Iran</country><wicri:regionArea>Correspondence address: Faculty of Pharmacy and Pharmaceutical Research Center, Shaheed Beheshti University of Medical Sciences, Tehran, P.O.Box 14155‐6153</wicri:regionArea><wicri:noRegion>P.O.Box 14155‐6153</wicri:noRegion></affiliation></author><author><name sortKey="Ghashang, Monireh" sort="Ghashang, Monireh" uniqKey="Ghashang M" first="Monireh" last="Ghashang">Monireh Ghashang</name><affiliation wicri:level="1"><country xml:lang="fr">Iran</country><wicri:regionArea>Faculty of Pharmacy and Pharmaceutical Research Center, Shaheed Beheshti University of Medical Sciences, Tehran, P.O.Box 14155‐6153</wicri:regionArea><wicri:noRegion>P.O.Box 14155‐6153</wicri:noRegion></affiliation></author><author><name sortKey="Ettehadi, Hossein Ali" sort="Ettehadi, Hossein Ali" uniqKey="Ettehadi H" first="Hossein Ali" last="Ettehadi">Hossein Ali Ettehadi</name><affiliation wicri:level="1"><country xml:lang="fr">Iran</country><wicri:regionArea>Faculty of Pharmacy and Pharmaceutical Research Center, Shaheed Beheshti University of Medical Sciences, Tehran, P.O.Box 14155‐6153</wicri:regionArea><wicri:noRegion>P.O.Box 14155‐6153</wicri:noRegion></affiliation></author><author><name sortKey="Ghalandari, Ruhollah" sort="Ghalandari, Ruhollah" uniqKey="Ghalandari R" first="Ruhollah" last="Ghalandari">Ruhollah Ghalandari</name><affiliation wicri:level="1"><country xml:lang="fr">Iran</country><wicri:regionArea>Faculty of Pharmacy and Pharmaceutical Research Center, Shaheed Beheshti University of Medical Sciences, Tehran, P.O.Box 14155‐6153</wicri:regionArea><wicri:noRegion>P.O.Box 14155‐6153</wicri:noRegion></affiliation></author></analytic><monogr></monogr><series><title level="j" type="main">Environmental Toxicology</title><title level="j" type="sub">12th International Symposium on Toxicity Assessment</title><title level="j" type="alt">ENVIRONMENTAL TOXICOLOGY</title><idno type="ISSN">1520-4081</idno><idno type="eISSN">1522-7278</idno><imprint><biblScope unit="vol">21</biblScope><biblScope unit="issue">4</biblScope><biblScope unit="page" from="349">349</biblScope><biblScope unit="page" to="354">354</biblScope><biblScope unit="page-count">6</biblScope><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><date type="published" when="2006-08">2006-08</date></imprint><idno type="ISSN">1520-4081</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">1520-4081</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="Teeft" xml:lang="en"><term>Acridine</term><term>Butylated</term><term>Butylated hydroxyanisole</term><term>Butylated hydroxytoluene</term><term>Control hepatocytes</term><term>Cytotoxicity</term><term>Dimethyl sulfoxide</term><term>Diphenyliodonium chloride</term><term>Emission wavelengths</term><term>Environmental toxicology</term><term>Glutathione</term><term>Hepatocyte</term><term>Hepatocyte toxicity</term><term>Hepatocytes</term><term>Inhibitor</term><term>Intracellular</term><term>Lipid</term><term>Lipid peroxidation</term><term>Lung cancer</term><term>Lysosomal</term><term>Membrane</term><term>Mitochondrial</term><term>Mitochondrial membrane</term><term>Molecular mechanisms</term><term>Oxygen uptake</term><term>Peroxidation</term><term>Pourahmad</term><term>Reactive</term><term>Reduction inhibitor</term><term>Reductive</term><term>Separate experiments</term><term>Tbars</term><term>Toxicity</term><term>Toxicology</term><term>Uorescence</term><term>Uorescence spectrophotometer</term><term>Uranyl</term><term>Uranyl acetate</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Addition of U(VI) (uranyl acetate) to isolated rat hepatocytes results in rapid glutathione oxidation, reactive oxygen species (ROS) formation, lipid peroxidation, decreased mitochondrial membrane potential, and lysosomal membrane rupture before hepatocyte lysis occurred. Cytotoxicity was prevented by ROS scavengers, antioxidants, and glutamine (ATP generator). Hepatocyte dichlorofluorescein oxidation was inhibited by mannitol (a hydroxyl radical scavenger) or butylated hydroxyanisole and butylated hydroxytoluene (antioxidants). Glutathione depleted hepatocytes were resistant to U(VI) toxicity and much less dichlorofluorescein oxidation occurred. Reduction of U(VI) by glutathione or cysteine in vitro was also accompanied by oxygen uptake and was inhibited by Ca(II) (a U(IV) or U(VI) reduction inhibitor). U(VI)‐induced cytotoxicity and ROS formation was also inhibited by Ca(II), which suggests that U(IV) and U(IV) GSH mediate ROS formation in isolated hepatocytes. The U(VI) reductive mechanism required for toxicity has not been investigated. Cytotoxicity was also prevented by cytochrome P450 inhibitors, particularly CYP 2E1 inhibitors, but not inhibitors of DT diaphorase or glutathione reductase. This suggests that P450 reductase and reduced cytochrome P450 contributes to U(VI) reduction to U(IV). In conclusion, U(VI) cytotoxicity is associated with mitochondrial/lysosomal toxicity by the reduced biological metabolites and ROS. © 2006 Wiley Periodicals, Inc. Environ Toxicol 21: 349–354, 2006.</div></front></TEI><affiliations><list><country><li>Canada</li><li>Iran</li></country></list><tree><country name="Iran"><noRegion><name sortKey="Pourahmad, Jalal" sort="Pourahmad, Jalal" uniqKey="Pourahmad J" first="Jalal" last="Pourahmad">Jalal Pourahmad</name></noRegion><name sortKey="Ettehadi, Hossein Ali" sort="Ettehadi, Hossein Ali" uniqKey="Ettehadi H" first="Hossein Ali" last="Ettehadi">Hossein Ali Ettehadi</name><name sortKey="Ghalandari, Ruhollah" sort="Ghalandari, Ruhollah" uniqKey="Ghalandari R" first="Ruhollah" last="Ghalandari">Ruhollah Ghalandari</name><name sortKey="Ghashang, Monireh" sort="Ghashang, Monireh" uniqKey="Ghashang M" first="Monireh" last="Ghashang">Monireh Ghashang</name><name sortKey="Pourahmad, Jalal" sort="Pourahmad, Jalal" uniqKey="Pourahmad J" first="Jalal" last="Pourahmad">Jalal Pourahmad</name></country><country name="Canada"><noRegion><name sortKey="Pourahmad, Jalal" sort="Pourahmad, Jalal" uniqKey="Pourahmad J" first="Jalal" last="Pourahmad">Jalal Pourahmad</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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