Role of metabolic activation and the TRPA1 receptor in the sensory irritation response to styrene and naphthalene

Abstract

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.

FIG. 1.

(A) Shown is the time of braking during baseline (−9 to 0 min) and exposure (0–15 min) to 75 ppm styrene in control and metyrapone-pretreated mice. Data are presented as mean ± SD; there were five to six mice per group. Duration of braking was significantly increased over baseline values in control mice throughout the entire exposure. Asterisks indicate the times at which the response in the metyrapone-pretreated mice was significantly lower than that in control mice. The solid bar indicates the times of exposure at which the duration of braking in metyrapone-pretreated mice was significantly greater than baseline. (B) Shown is the time of braking during baseline (−9 to 0 min) and exposure (0–15 min) to 7 ppm naphthalene in control and metyrapone-pretreated mice. Data are presented as mean ± SD; there were five to six mice per group. Duration of braking was significantly increased over baseline values in control mice throughout the entire exposure. Asterisks indicate the times at which the response in the metyrapone-pretreated mice was significantly lower than that in control mice. At no time during the exposure was the duration of braking in metyrapone-pretreated mice significantly greater than baseline.

FIG. 2.

(A) Shown is the time of braking during baseline (−9 to 0 min) and exposure (0–15 min) to 75 ppm styrene in wild-type and TRPA1−/− mice. Data are presented as mean ± SD; there were four mice per group. Duration of braking was significantly increased over baseline values in wild-type mice throughout the entire exposure. Asterisks indicate the times at which the response in the TRPA1−/− mice was significantly lower than that in wild-type mice. The solid bar indicates the times of exposure at which the duration of braking TRPA1−/− mice was significantly greater than baseline. (B) Shown is the time of braking during baseline (−9 to 0 min) and exposure (0–15 min) to 7 ppm naphthalene in wild-type and TRPA1−/− mice. Data are presented as mean ± SD; there were four mice per group. Duration of braking was significantly increased over baseline values in wild-type mice throughout the entire exposure. Asterisks indicate the times at which the response in the TRPA1−/− mice was significantly lower than that in wild-type mice. The solid bar indicates the times of exposure at which the duration of braking in metyrapone-pretreated mice was significantly greater than baseline.