Goetz Amber K, Dix David J
National Center for Computational Toxicology, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA.
Toxicol Appl Pharmacol. 2009 Jul 1;238(1):80-9. doi: 10.1016/j.taap.2009.04.016. Epub 2009 May 3.
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 timepoints 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 of 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. Differentially expressed genes included the Phase I xenobiotic, fatty acid, sterol and steroid metabolism genes Cyp2b2 and CYP2B6, Cyp3a1 and CYP3A4, and Cyp4a22 and CYP4A11; Phase II conjugation enzyme genes 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 changes in serum testosterone and adverse reproductive outcomes observed in rat studies, and may be relevant to human risk assessment.
三唑类抗真菌剂腈菌唑、丙环唑和三唑酮在啮齿动物体内模型中会引起不同程度的肝毒性，并扰乱类固醇激素稳态。为了确定在多个时间点和各种研究设计中持续受到调节的生物学途径，对来自三项独立研究的大鼠肝脏进行了基因表达谱分析，这些研究中的三唑治疗组涵盖了单次口服灌胃暴露后6小时，直至通过饲料进行的产前至成年期暴露。为了探索物种间反应的保守性，将大鼠肝脏研究中的基因表达与暴露于三唑类药物的大鼠和人类原代肝细胞的体外数据进行了比较。来自33个不同治疗组和135个样本（微阵列）的三唑类药物毒理基因组数据确定了数千个探针集和数十条在时间、剂量和物种间差异表达的途径——其中许多途径是所有三种三唑类药物共有的，或者在啮齿动物和人类之间是保守的。常见且保守的途径包括雄激素和雌激素代谢、通过CAR和PXR的外源性物质代谢信号传导以及CYP介导的代谢。差异表达的基因包括I相外源性物质、脂肪酸、甾醇和类固醇代谢基因Cyp2b2和CYP2B6、Cyp3a1和CYP3A4、Cyp4a22和CYP4A11；II相结合酶基因Ugt1a1和UGT1A1；以及III相ABC转运蛋白基因Abcb1和ABCB1。所有三种三唑类药物在肝脏和肝细胞中引起的基因表达变化都集中在调节脂质、甾醇和类固醇稳态的生物学途径中，这确定了啮齿动物和人类之间潜在的共同作用模式。肝脏甾醇和类固醇代谢的调节是大鼠研究中观察到的血清睾酮变化和不良生殖结果的一种合理作用模式，并且可能与人类风险评估相关。
