Thiol oxidation and cytochrome P450-dependent metabolism of CCl4 triggers Ca2+ release from liver microsomes

Biochemistry
D Stoyanovsky, A I Cederbaum

Abstract

Elevation of cytosolic calcium levels has been shown to occur after exposure to hepatotoxins such as CCl4. This has been associated with inhibition of the Ca2+, Mg(2+)-ATPase which pumps calcium into the endoplasmic reticulum. Elevated cytosolic Ca2+ may also result from activation of calcium releasing channels. In the presence of NADPH, CCl4 produced a concentration-dependent release of calcium from liver microsomes after a lag period. The lag period was shorter with microsomes from pyrazole-treated rats in which CYP2E1 is induced, as compared to saline microsomes. The calcium releasing process appears to be very sensitive to activation by CCl4 as effective concentrations (e.g., 50 microM) did not affect the Ca2+, Mg(2+)-ATPase or produce lipid peroxidation. Inhibition of the CCl4-induced release of calcium by 4-methylpyrazole and by anti-CYP2E1 IgG, and the requirement for NADPH, indicates that CCl4 metabolism is required for the activation of calcium release. The lag period for CCl4-induced release of calcium was associated with the time required to deplete alpha-tocopherol from the microsomal membranes; however, lipid peroxidation was not observed at these levels of CCl4, and the lag period for CCl4-induced release of calci...Continue Reading

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Citations

Jun 23, 1999·Toxicology Letters·D A Stoyanovsky, A I Cederbaum
May 20, 1998·Free Radical Biology & Medicine·D A Stoyanovsky, A I Cederbaum
Jun 2, 1998·Free Radical Biology & Medicine·J BustamanteB H Rihn
Jul 5, 2005·Expert Opinion on Investigational Drugs·J WuM A Zern
Jan 5, 2005·Archives of Biochemistry and Biophysics·Paul Waring
Dec 6, 2005·Experimental and Toxicologic Pathology : Official Journal of the Gesellschaft Für Toxikologische Pathologie·Evgeny A MininHermann Herbst
Feb 13, 1999·Developmental Biology·N RosemblitA R Marks
Jan 24, 1998·Archives of Biochemistry and Biophysics·M Díaz-MuñozR Hernández-Muñoz
Dec 9, 2010·Human & Experimental Toxicology·Leo Lap Yan WongJennifer Man-Fan Wan
Sep 1, 2007·Journal of Environmental Science and Health. Part C, Environmental Carcinogenesis & Ecotoxicology Reviews·Mary K ManibusanDavid A Eastmond
Aug 22, 2020·Journal of Experimental Pharmacology·Betelhem Anteneh AdamuMebrahtom Gebrelibanos Hiben
Oct 17, 2008·Journal of Agricultural and Food Chemistry·Siriluck PonsuksiliKlaus Wimmers

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