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Inhibition of vinyl carbamate-induced hepatotoxicity, mutagenicity, and tumorigenicity by isopropyl-2-(1,3-dithietane-2-ylidene)-2-[N-(4-methylthiazol-2-yl)carbam oyl]acetate (YH439)

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Authors
Kim, Seong Gon; Surh, Young-Joon; Sohn, Yeowon; Yoo, Joong-Keun; Lee, Jong Wook; Liem, Amy; Miller, James A.
Issue Date
1998-04
Citation
Carcinogenesis, Vol.19 No.4, pp.687-690
Abstract
Isopropyl-2-(1,3-dithietane-2-ylidene)-2-[N-(4-methylthiazol-2-yl)carbamoyl]acetate (YH439) is a novel dithioylidene malonate derivative developed for the treatment of hepatic injury, The compound has been found to down-regulate the expression of hepatic cytochrome P-450 2E1 (CYP2E1) at the transcriptional level (8), Certain organosulfur compounds present in garlic elicit protective effects on chemically induced carcinogenesis and mutagenesis and their chemopreventive activities are associated in part with inhibition of CYP2E1, As part of a program to determine the likely chemopreventive potential of YH439, we initially examined its effects on hepatotoxicity induced by vinyl carbamate (VC), a proximate carcinogen that is preferentially bioactivated by CYP2E1, A single i.p. injection of VC (125 mg/kg body wt) to male Sprague-Dawley rats resulted in severe hepatic lesions as demonstrated by elevated levels of serum enzymes such as alanine aminotransferase and aspartate aminotransferase. Histopathological evaluation of liver sections from VC-treated animals revealed that the hepatic damage mainly consisted of centrilobular necrosis with sinusoidal congestion, Oral administration of YH439 (200 mg/kg body wt) to male Sprague-Dawley rats 2 days, 1 day and 4 h prior to VC completely prevented the hepatic damage caused by this carcinogen. In another experiment, rat hepatic microsome-mediated bacterial mutagenicity of VC was suppressed by YH439 in a dose-related manner, Furthermore, pretreatment of female CD-1 mice with YH439 by gastric intubation resulted in diminution of VC-induced skin carcinogenesis.
ISSN
0143-3334
URI
https://hdl.handle.net/10371/172921
DOI
https://doi.org/10.1093/carcin/19.4.687
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Graduate School of Convergence Science and Technology (융합과학기술대학원)Dept. of Molecular and Biopharmaceutical Sciences (분자의학 및 바이오제약학과)Journal Papers (저널논문_분자의학 및 바이오제약학과)
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