Toxicology Program, Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut 06269, USA.
Toxicol Sci. 2010 Jun;115(2):589-95. doi: 10.1093/toxsci/kfq057. Epub 2010 Feb 22.
The current study was aimed at examining the role of cytochrome P450 (CYP450) activation and the electrophile-sensitive transient receptor potential ankyrin 1 receptor (TRPA1) in mediating the sensory irritation response to styrene and naphthalene. Toward this end, the sensory irritation to these vapors was measured in female C57Bl/6J mice during 15-min exposure via plethysmographic measurement of the duration of braking at the onset of each expiration. The sensory irritation response to 75 ppm styrene and 7 ppm naphthalene was diminished threefold or more in animals pretreated with the CYP450 inhibitor metyrapone, providing evidence of the role of metabolic activation in the response to these vapors. The sensory irritation response to styrene (75 ppm) and naphthalene (7.6 ppm) was virtually absent in TRPA1-/- knockout mice, indicating the critical role of this receptor in mediating the response. Thus, these results support the hypothesis that styrene and naphthalene vapors initiate the sensory irritation response through TRPA1 detection of their CYP450 metabolites.
本研究旨在探讨细胞色素 P450（CYP450）激活和亲电敏感瞬时受体电位锚蛋白 1 受体（TRPA1）在介导苯乙烯和萘对感觉刺激反应中的作用。为此，通过测量每次呼气开始时制动持续时间的体积描记法，在雌性 C57Bl/6J 小鼠中测量这些蒸气在 15 分钟暴露期间的感觉刺激。用 CYP450 抑制剂甲吡酮预处理的动物，苯乙烯（75 ppm）和萘（7 ppm）的感觉刺激反应减少了三倍或更多，这为这些蒸气的反应中代谢激活的作用提供了证据。TRPA1-/- 基因敲除小鼠对苯乙烯（75 ppm）和萘（7.6 ppm）的感觉刺激反应几乎不存在，表明该受体在介导反应中的关键作用。因此，这些结果支持这样的假设，即苯乙烯和萘蒸气通过 TRPA1 检测它们的 CYP450 代谢物引发感觉刺激反应。
