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.