Three conazoles increase hepatic microsomal retinoic acid metabolism and decrease mouse hepatic retinoic acid levels in vivo
Journal
Toxicology and Applied Pharmacology
Journal Volume
234
Journal Issue
2
Pages
143-155
Date Issued
2009
Author(s)
Abstract
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 of the metabolism of all trans-retinoic acid (atRA), a vitamin A metabolite with cancer-preventative properties (Ward et al., Toxicol. Pathol. 2006; 34:863-78). The goals of this study were to examine effects of propiconazole, triadimefon, and myclobutanil, three triazole-containing conazoles, on the microsomal metabolism of atRA, the associated hepatic cytochrome P450 (P450) enzyme(s) involved in atRA metabolism, and their effects on hepatic atRA levels in vivo. The in vitro metabolism of atRA was quantitatively measured in liver microsomes from male CD-1 mice following four daily intraperitoneal injections of propiconazole (210?mg/kg/d), triadimefon (257?mg/kg/d) or myclobutanil (270?mg/kg/d). The formation of both 4-hydroxy-atRA and 4-oxo-atRA were significantly increased by all three conazoles. Propiconazole-induced microsomes possessed slightly greater metabolizing activities compared to myclobutanil-induced microsomes. Both propiconazole and triadimefon treatment induced greater formation of 4-hydroxy-atRA compared to myclobutanil treatment. Chemical and immuno-inhibition metabolism studies suggested that Cyp26a1, Cyp2b, and Cyp3a, but not Cyp1a1 proteins were involved in atRA metabolism. Cyp2b10/20 and Cyp3a11 genes were significantly over-expressed in the livers of both triadimefon- and propiconazole-treated mice while Cyp26a1, Cyp2c65 and Cyp1a2 genes were over-expressed in the livers of either triadimefon- or propiconazole-treated mice, and Cyp2b10/20 and Cyp3a13 genes were over-expressed in the livers of myclobutanil-treated mice. Western blot analyses indicated conazole induced-increases in Cyp2b and Cyp3a proteins. All three conazoles decreased hepatic atRA tissue levels ranging from 45-67%. The possible implications of these changes in hepatic atRA levels on cell proliferation in the mouse tumorigenesis process are discussed.
Subjects
All trans retinoic acid; Conazoles; Myclobutanil; P450; Propiconazole; Triadimefon
SDGs
Other Subjects
4 hydroxyretinoic acid; 4 oxomethylretinoic acid; 4 oxoretinoic acid; alpha naphthoflavone; cytochrome P450; cytochrome P450 1A1; cytochrome P450 1A2; cytochrome P450 26A1; cytochrome P450 2B; cytochrome p450 2b10; cytochrome P450 2b20; cytochrome P450 2c65; cytochrome P450 3A; cytochrome P450 3A11; diethyldithiocarbamic acid; fungicide; ketoconazole; metyrapone; myclobutanil; propiconazole; quercetin; reduced nicotinamide adenine dinucleotide phosphate; retinoic acid; sterol 14alpha demethylase; ticlopidine; triadimefon; triazole derivative; unclassified drug; animal experiment; animal tissue; article; body weight; cell proliferation; controlled study; drug hydroxylation; drug metabolism; drug structure; drug synthesis; enzyme induction; enzyme inhibition; gene expression; high performance liquid chromatography; IC 50; in vitro study; in vivo study; isomerization; liquid chromatography; liver carcinogenesis; liver hypertrophy; liver microsome; liver toxicity; liver weight; male; metabolic inhibition; mouse; nonhuman; real time polymerase chain reaction; reverse transcription; RNA extraction; single drug dose; statistical analysis; tandem mass spectrometry; Western blotting; Animals; Blotting, Western; Body Weight; Chromatography, High Pressure Liquid; Cytochrome P-450 Enzyme System; Fungicides, Industrial; Gene Expression Profiling; Liver; Male; Mice; Microsomes, Liver; Nitriles; Organ Size; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Spectrometry, Mass, Electrospray Ionization; Tretinoin; Triazoles; Atra; Mus
Type
journal article