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Toxicogenomic Effects Common to Triazole Antifungals and Conserved Between Rats and Humans
Citation:
GOETZ, A. AND D. J. DIX. Toxicogenomic Effects Common to Triazole Antifungals and Conserved Between Rats and Humans. TOXICOLOGY AND APPLIED PHARMACOLOGY. Academic Press Incorporated, Orlando, FL, 238(1):80-9, (2009).
Impact/Purpose:
Comparison between liver and rat primary hepatocytes showed a targeted effect on genes involved in early fatty acid catabolism, and to a lesser degree on phase III transporters and sterol metabolism. Common biological processes were affected in rat and human primary hepatocytes, however effects were triazole-specific to each system. The subsets of genes involved in fatty acid catabolism/lipid homeostasis, phase III transporters, and metabolism of testosterone are robust candidates for biomarkers defining a part of the mechanisms of action for disrupting testosterone homeostasis. It is possible that these gene expression changes denote not only shifts in lipogenesis to fatty acid oxidation for increased energy production, and increased expression of phase III transporters for the uptake and excretion of triazoles in the hepatocytes, but also mechanisms of triazole toxicity common across the triazoles.
Description:
The triazole antifungals myclobutanil, propiconazole and triadimefon cause varying degrees of hepatic toxicity and disrupt steroid hormone homeostasis in rodent in vivo models. To identify biological pathways consistently modulated across multiple time-points and various study designs, gene expression profiling was conducted on rat livers from three separate studies with triazole treatment groups ranging from 6 h after a single oral gavage exposure, to prenatal to adult exposures via feed. To explore conservation of responses across species, gene expression from the rat liver studies were compared to in vitro data from rat and human primary hepatocytes exposed to the triazoles. Toxicogenomic data on triazoles from 33 different treatment groups and 135 samples (microarrays) identified thousands of probe sets and dozens pathways differentially expressed across time, dose, and species- many of these were common to all three triazoles, or conserved between rodents and humans. Common and conserved pathways included androgen and estrogen metabolism, xenobiotic metabolism signaling through CAR and PXR, and CYP mediated metabolism. Many of the common and conserved differentially expressed genes in this study are regulated by the nuclear receptors CAR and PXR: CYP genes significant to phase I xenobiotic, fatty acid, sterol and steroid metabolism (Cyp2b2 and CYP2B6; Cyp3a1 and CYP3A4; Cyp4a22 and CYP4A11); phase II conjugation enzymes (Ugt1a1 and UGT1A1); and phase III ABC transporter genes (Abcb1 and ABCB1). Gene expression changes caused by all three triazoles in liver and hepatocytes were concentrated in biological pathways regulating lipid, sterol and steroid homeostasis, identifying a potential common mode of action conserved between rodents and humans. Modulation of hepatic sterol and steroid metabolism is a plausible mode of action for the changes in serum testosterone observed in rat studies and linked to adverse reproductive outcomes.
URLs/Downloads:
Toxicogenomic Effects Common to Triazole Antifungals and ConservedBetween Rats and Humans