INHIBITION OF VINYL CARBAMATE-INDUCED HEPATOTOXICITY, MUTAGENICITY, AND TUMORIGENICITY BY DENE)-2-[N-(4-METHYLTHIAZOL-2-YL)CARBAMOYL]ACETATE (YH439)

dene)-2-[N-(4-methylthiazol-2-yl)carbamoyl]acetate (YH439) is a novel dithioylidene malonate derivative developed for the treatment of hepat ic 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 protecti ve effects on chemically induced carcinogenesis and mutagenesis and th eir chemopreventive activities are associated in part with inhibition of CYP2E1, As part of a program to determine the likely chemopreventiv e potential of YH439, we initially examined its effects on hepatotoxic ity induced by vinyl carbamate (VC), a proximate carcinogen that is pr eferentially bioactivated by CYP2E1, A single i.p. injection of VC (12 5 mg/kg body wt) to male Sprague-Dawley rats resulted in severe hepati c lesions as demonstrated by elevated levels of serum enzymes such as alanine aminotransferase and aspartate aminotransferase. Histopatholog ical evaluation of liver sections from VC-treated animals revealed tha t the hepatic damage mainly consisted of centrilobular necrosis with s inusoidal 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 complet ely 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, pret reatment of female CD-1 mice with YH439 by gastric intubation resulted in diminution of VC-induced skin carcinogenesis.