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CHARACTERIZATION OF CYPS IN THE METABOLISM OF ALL TRANS RETINOIC ACID BY LIVER MICROSOMES FROM MICE TREATED WITH CONAZOLES
CHEN, P., W. PADGETT, T. MOORE, W. M. WINNIK, S. Y. THAI, S. D. HESTER, AND S. NESNOW. CHARACTERIZATION OF CYPS IN THE METABOLISM OF ALL TRANS RETINOIC ACID BY LIVER MICROSOMES FROM MICE TREATED WITH CONAZOLES. Presented at Society of Toxicology Annual Meeting, Seattle, WA, March 16 - 20, 2008.
Conazoles are fungicides used in crop protection and as pharmaceuticals. Triadimefon and propiconazole are hepatotumorigenic in mice, while myclobutanil is not. Previous toxicogenomic studies suggest that alteration of the retinoic acid metabolism pathway may involve in conazole-induced hepatotumorigenesis. This study was to examine the atRA metabolism by liver microsomes from conazole-treated mice, and characterize the associated hepatic cytochrome P450 (Cyp) enzyme(s) involved in atRA metabolism. In vitro metabolism of atRA was assessed in liver microsomes from male CD-1 mice following four daily intraperitoneal (IP) injection of propiconazole (210 mg/kg/d), triadimefon (257 mg/kg/d) or myclobutanil (270 mg/kg/d), and total atRA metabolism activity (sum of 4-OH- and 4-oxo-atRA) was quantified with HPLC. Formation of 4-OH-, 4-oxo-atRA, and total atRA metabolism were significantly increased by all three conazoles. Propiconazole-induced microsomes possessed greater metabolizing activities based on total atRA metabolism and 4-OH-atRA formation compared to myclobutanil-induced microsomes. Cyp26al, Cyp2b10(20), Cyp3a11, Cyp2c65 and Cyp1a2 genes were significantly over-expressed in the livers from propiconazole- or triadimefon-treated mice, while only Cyp2b10(20) and Cyp3a13 genes were over-expressed in myclobutanil-treated mice. Chemical and immuno-inhibition studies suggested that Cyp26a1, Cyp3a and Cyp2b were involved in atRA metabolism. The over-expression of Cyp26a1, Cyp2b10(20) and Cyp3a11 enzymes are consistent with increased atRA metabolism induced by conazoles in mouse liver. The implications of these changes with respect to reduced atRA levels in hepatic tissues suggest that it might be a necessary event in conazole-induced hepatotumorigenesis.
This study was to examine the atRA metabolism by liver microsomes from conazole-treated mice, and characterize the associated hepatic cytochrome P450 (Cyp) enzyme(s) involved in atRA metabolism.
Record Details:Record Type: DOCUMENT (PRESENTATION/EXTENDED ABSTRACT)
Organization:U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LAB
ENVIRONMENTAL CARCINOGENESIS DIVISION