Morris John B, Buckpitt Alan R
Toxicology Program, Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut, USA.
Toxicol Sci. 2009 Oct;111(2):383-91. doi: 10.1093/toxsci/kfp138. Epub 2009 Jul 31.
Naphthalene is a nasal toxicant and carcinogen in the rat. Upper respiratory tract (URT) uptake of naphthalene was measured in the male and female F344 rat at exposure concentrations of 1, 4, 10, or 30 ppm at inspiratory flow rates of 150 or 300 ml/min. To assess the potential importance of nasal cytochrome P450 (CYP) metabolism, groups of rats were pretreated with the CYP inhibitor 5-phenyl-1-pentyne (PP) (100 mg/kg, ip). In vitro metabolism of naphthalene was similar in nasal tissues from both genders and was reduced by 80% by the inhibitor. URT uptake in female rats was concentration dependent with uptake efficiencies (flow 150 ml/min) of 56, 40, 34, and 28% being observed at inspired concentrations of 1, 4, 10, and 30 ppm, respectively. A similar effect was observed in male rats (flow 150 ml/min) with uptake efficiencies of 57, 49, 37, and 36% being observed. Uptake was more efficient in the male than female rat, likely due to their larger size (226 vs. 144 g). Uptake of naphthalene was significantly reduced by inhibitor pretreatment with the effect being greater at the lower inspired concentrations. Specifically, in pretreated female rats (150 ml/min), URT uptake averaged 25, 29, and 26% at inspired concentrations of 4, 10, and 30 ppm, respectively. Thus, the concentration dependence of uptake was virtually abolished by PP pretreatment. These results provide evidence that nasal CYP metabolism of naphthalene contributes to URT scrubbing of this vapor and is also involved in the concentration dependence of uptake that is observed.
萘是大鼠的一种经鼻毒性物质和致癌物。在雄性和雌性F344大鼠中，于吸气流量为150或300 ml/min、暴露浓度为1、4、10或30 ppm的条件下测量了萘对上呼吸道（URT）的摄取情况。为评估鼻细胞色素P450（CYP）代谢的潜在重要性，对几组大鼠进行了CYP抑制剂5-苯基-1-戊炔（PP）（100 mg/kg，腹腔注射）预处理。萘在两性鼻组织中的体外代谢情况相似，且该抑制剂使其代谢降低了80%。雌性大鼠的URT摄取呈浓度依赖性，在吸入浓度为1、4、10和30 ppm时，摄取效率（流量150 ml/min）分别为56%、40%、34%和28%。在雄性大鼠（流量150 ml/min）中观察到了类似的效应，摄取效率分别为57%、49%、37%和36%。雄性大鼠的摄取效率高于雌性大鼠，这可能是由于其体型较大（226 g对144 g）。抑制剂预处理显著降低了萘的摄取，在较低吸入浓度下效果更明显。具体而言，在预处理的雌性大鼠（150 ml/min）中，吸入浓度为4、10和30 ppm时，URT摄取平均分别为25%、29%和26%。因此，PP预处理几乎消除了摄取的浓度依赖性。这些结果证明，萘的鼻CYP代谢有助于对上呼吸道中该蒸气的清除，并且也参与了所观察到的摄取浓度依赖性。
