Role of metabolic activation and the TRPA1 receptor in the sensory irritation response to styrene and naphthalene.
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.
Lanosa
Michael J
MJ
Toxicology Program, Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut 06269, USA.
Willis
Daniel N
DN
Jordt
Sven
S
Morris
John B
JB
D000818:Animals; D001711:Biotransformation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D007509:Irritants / Q000493:pharmacokinetics / Q000633:toxicity*; D008797:Metyrapone / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009281:Naphthalenes / Q000493:pharmacokinetics / Q000633:toxicity*; D009831:Olfactory Mucosa / Q000187:drug effects* / Q000378:metabolism; D010991:Plethysmography; D012119:Respiration / Q000187:drug effects; D020058:Styrene / Q000493:pharmacokinetics / Q000633:toxicity*; D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels / Q000378:metabolism*
D004791:Enzyme Inhibitors; D007509:Irritants; D009281:Naphthalenes; D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels; C475685:Trpa1 protein, mouse; C031721:naphthalene; D020058:Styrene; D008797:Metyrapone