Inhibitory effects of isopropyl-2-(1,3-dithietane-2-ylidene)-2-[ N-(4-methylthiazol-2-yl)carbamoyl]acetate (YH439) on benzo[ a]pyrene-induced skin carcinogenesis and micronucleated reticulocyte formation in mice

Abstract

Recently, a great deal of attention has been devoted to organosulfur compounds with potential cancer chemopreventive properties. Many sulfur-containing substances present in Brassica plants have been reported to possess striking anticarcinogenic and antimutagenic activities. Besides naturally occurring organosulfur compounds, certain synthetic sulfur-containing pharmaceuticals, such as oltipraz and sulindac, are known to exert substantial chemopreventive or chemoprotective effects. Isopropyl-2-(1,3-dithietane-2-ylidene)-2-[ N-(4-methylthiazol-2-yl)carbamoyl]acetate (YH439) was initially developed for its possible use as a hepatoprotectant. The compound has been found to up-regulate the expression of cytochrome P-450 IA1 [I.J. Lee, K.S. Jeong, B.J. Roberts, A.T. Kallarakal, P. Fernandez-Salguero, F.J. Gonzalez, B.J. Song, Transcriptional induction of the cytochrome P-450 1A1 gene by a thiazolium compound YH439, Mol. Pharmacol. 49 (1996) 980–988.] which plays a pivotal role in metabolism of the majority of polycyclic aromatic carcinogens and mutagens, such as benzo[ a]pyrene (B[ a]P). In the present study, we found that oral administration of YH439 to CD-1 mice significantly suppressed B[ a]P-initiated skin tumorigenesis. B[ a]P-induced formation of micronuclei in mouse peripheral reticulocytes was also attenuated by YH439 pretreatment. Likewise, diallyl sulfide, a major volatile thioether present in garlic, also protected against B[ a]P-induced skin tumorigenesis and micronucleated reticulocyte formation in mice.