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S-(1,2,2-trichlorovinyl)-L-cysteine sulfoxide, a reactive metabolite of S-(1,2,2-Trichlorovinyl)-L-cysteine formed in rat liver and kidney microsomes, is a potent nephrotoxicant.
J Pharmacol Exp Ther. 2007 Jun; 321(3):1095-101.JP

Abstract

Previously, we have provided evidence that cytochromes P450 (P450s) and flavin-containing monooxygenases (FMOs) are involved in the oxidation of S-(1,2,2-trichlorovinyl)-L-cysteine (TCVC) in rabbit liver microsomes to yield the reactive metabolite TCVC sulfoxide (TCVCS). Because TCVC is a known nephrotoxic metabolite of tetrachloroethylene, the nephrotoxic potential of TCVCS in rats and TCVCS formation in rat liver and kidney microsomes were investigated. At 5 mM TCVC, rat liver microsomes formed TCVCS at a rate nearly 5 times higher than the rate measured with rat kidney microsomes, whereas at 1 mM TCVC only the liver activity was detectable. TCVCS formation in liver and kidney microsomes was dependent upon the presence of NADPH and was inhibited by the addition of methimazole or 1-benzylimidazole, but not superoxide dismutase, catalase, KCN, or deferoxamine, consistent with the involvement of both FMOs and P450s. Rats given TCVCS at 230 micromol/kg i.p. exhibited acute tubular necrosis at 2 and 24 h after treatment, and they had elevated blood urea nitrogen levels at 24 h, whereas TCVC was a much less potent nephrotoxicant than TCVCS. Furthermore, pretreatment with aminooxyacetic acid enhanced TCVC toxicity. In addition, reduced nonprotein thiol concentrations in the kidney were decreased by nearly 50% 2 h after TCVCS treatment compared with saline-treated rats, whereas the equimolar dose of TCVC had no effect on kidney nonprotein thiol status. No significant lesions or changes in nonprotein thiol status were observed in liver with either TCVC or TCVCS. Collectively, the results suggest that TCVCS may play a role in TCVC-induced nephrotoxicity.

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Authors+Show Affiliations

Elfarra AA
Department of Comparative Biosciences and Center for Molecular and Environmental Toxicology, University of Wisconsin, Madison, Wisconsin, USA. elfarra@svm.vetmed.wisc.edu
Krause RJ
No affiliation info available

MeSH

Alanine TransaminaseAminooxyacetic AcidAnimalsAspartate AminotransferasesBlood GlucoseBlood Urea NitrogenCysteineCytochrome P-450 Enzyme InhibitorsCytochrome P-450 Enzyme SystemEnzyme InhibitorsGlycosuriaImidazolesKidneyLiverMaleMethimazoleMicrosomesMicrosomes, LiverRatsRats, Sprague-DawleySulfhydryl CompoundsSulfoxidesgamma-Glutamyltransferase

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

17347324

Citation

Elfarra, Adnan A., and Renee J. Krause. "S-(1,2,2-trichlorovinyl)-L-cysteine Sulfoxide, a Reactive Metabolite of S-(1,2,2-Trichlorovinyl)-L-cysteine Formed in Rat Liver and Kidney Microsomes, Is a Potent Nephrotoxicant." The Journal of Pharmacology and Experimental Therapeutics, vol. 321, no. 3, 2007, pp. 1095-101.
Elfarra AA, Krause RJ. S-(1,2,2-trichlorovinyl)-L-cysteine sulfoxide, a reactive metabolite of S-(1,2,2-Trichlorovinyl)-L-cysteine formed in rat liver and kidney microsomes, is a potent nephrotoxicant. J Pharmacol Exp Ther. 2007;321(3):1095-101.
Elfarra, A. A., & Krause, R. J. (2007). S-(1,2,2-trichlorovinyl)-L-cysteine sulfoxide, a reactive metabolite of S-(1,2,2-Trichlorovinyl)-L-cysteine formed in rat liver and kidney microsomes, is a potent nephrotoxicant. The Journal of Pharmacology and Experimental Therapeutics, 321(3), 1095-101.
Elfarra AA, Krause RJ. S-(1,2,2-trichlorovinyl)-L-cysteine Sulfoxide, a Reactive Metabolite of S-(1,2,2-Trichlorovinyl)-L-cysteine Formed in Rat Liver and Kidney Microsomes, Is a Potent Nephrotoxicant. J Pharmacol Exp Ther. 2007;321(3):1095-101. PubMed PMID: 17347324.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - S-(1,2,2-trichlorovinyl)-L-cysteine sulfoxide, a reactive metabolite of S-(1,2,2-Trichlorovinyl)-L-cysteine formed in rat liver and kidney microsomes, is a potent nephrotoxicant. AU - Elfarra,Adnan A, AU - Krause,Renee J, Y1 - 2007/03/08/ PY - 2007/3/10/pubmed PY - 2007/7/31/medline PY - 2007/3/10/entrez SP - 1095 EP - 101 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 321 IS - 3 N2 - Previously, we have provided evidence that cytochromes P450 (P450s) and flavin-containing monooxygenases (FMOs) are involved in the oxidation of S-(1,2,2-trichlorovinyl)-L-cysteine (TCVC) in rabbit liver microsomes to yield the reactive metabolite TCVC sulfoxide (TCVCS). Because TCVC is a known nephrotoxic metabolite of tetrachloroethylene, the nephrotoxic potential of TCVCS in rats and TCVCS formation in rat liver and kidney microsomes were investigated. At 5 mM TCVC, rat liver microsomes formed TCVCS at a rate nearly 5 times higher than the rate measured with rat kidney microsomes, whereas at 1 mM TCVC only the liver activity was detectable. TCVCS formation in liver and kidney microsomes was dependent upon the presence of NADPH and was inhibited by the addition of methimazole or 1-benzylimidazole, but not superoxide dismutase, catalase, KCN, or deferoxamine, consistent with the involvement of both FMOs and P450s. Rats given TCVCS at 230 micromol/kg i.p. exhibited acute tubular necrosis at 2 and 24 h after treatment, and they had elevated blood urea nitrogen levels at 24 h, whereas TCVC was a much less potent nephrotoxicant than TCVCS. Furthermore, pretreatment with aminooxyacetic acid enhanced TCVC toxicity. In addition, reduced nonprotein thiol concentrations in the kidney were decreased by nearly 50% 2 h after TCVCS treatment compared with saline-treated rats, whereas the equimolar dose of TCVC had no effect on kidney nonprotein thiol status. No significant lesions or changes in nonprotein thiol status were observed in liver with either TCVC or TCVCS. Collectively, the results suggest that TCVCS may play a role in TCVC-induced nephrotoxicity. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/17347324/S__122_trichlorovinyl__L_cysteine_sulfoxide_a_reactive_metabolite_of_S__122_Trichlorovinyl__L_cysteine_formed_in_rat_liver_and_kidney_microsomes_is_a_potent_nephrotoxicant_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=17347324 DB - PRIME DP - Unbound Medicine ER -
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