Three conazoles increase hepatic microsomal retinoic acid metabolism and decrease mouse hepatic retinoic acid levels in vivo

摘要: Conazoles are fungicides used in agriculture and as pharmaceuticals. In a previous toxicogenomic study of triazole-containing conazoles we found gene expression changes consistent with the alteration metabolism all trans-retinoic acid (atRA), vitamin A metabolite cancer-preventative properties (Ward et al., Toxicol. Pathol. 2006; 34:863-78). The goals this were to examine effects propiconazole, triadimefon, myclobutanil, three conazoles, on microsomal atRA, associated hepatic cytochrome P450 (P450) enzyme(s) involved atRA metabolism, their levels vivo. vitro was quantitatively measured liver microsomes from male CD-1 mice following four daily intraperitoneal injections propiconazole (210 mg/kg/d), triadimefon (257 mg/kg/d) or myclobutanil (270 mg/kg/d). formation both 4-hydroxy-atRA 4-oxo-atRA significantly increased by conazoles. Propiconazole-induced possessed slightly greater metabolizing activities compared myclobutanil-induced microsomes. Both treatment induced treatment. Chemical immuno-inhibition studies suggested that Cyp26a1, Cyp2b, Cyp3a, but not Cyp1a1 proteins metabolism. Cyp2b10/20 Cyp3a11 genes over-expressed livers triadimefon- propiconazole-treated while Cyp2c65 Cyp1a2 either mice, Cyp3a13 myclobutanil-treated mice. Western blot analyses indicated conazole induced-increases Cyp2b Cyp3a proteins. All decreased tissue ranging 45-67%. possible implications these cell proliferation mouse tumorigenesis process discussed.