Waidyanatha Suramya, Rappaport Stephen M
Department of Environmental Sciences and Engineering, School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7431, United States.
Chem Biol Interact. 2008 Mar 27;172(2):105-14. doi: 10.1016/j.cbi.2008.01.004. Epub 2008 Jan 16.
The toxicity of naphthalene in rodents has been attributed to the reactive metabolites naphthalene-1,2-oxide (NPO), 1,2-naphthoquinone (1,2-NPQ) and 1,4-naphthoquinone (1,4-NPQ). Differences in the formation of these reactive metabolites in different species can shed light on the mechanism by which naphthalene exerts its toxicity. Protein adducts allow investigators to study the disposition of reactive metabolites that cannot be measured directly. We measured cysteinyl adducts of the above metabolites in hemoglobin (Hb) and albumin (Alb) from the blood of male Swiss Webster mice dosed with 1.56-200mg naphthalene/kg b.w. Levels of NPO adducts (designated as NPO1-Hb, NPO2-Hb, NPO1-Alb and NPO2-Alb) increased nonlinearly with the administered dose; levels of Alb adducts were higher than those of Hb adducts; levels of NPO1 adducts were higher than those of NPO2 adducts. Levels of NPQ adducts (1,2-NPQ-Alb, 1,4-NPQ-Alb, 1,2-NPQ-Hb and 1,4-NPQ-Hb) were lower than those of NPO. Although NPQ-Alb increased with doses above 12.5 mg naphthalene/kg body wt. (b.w.), levels of NPQ-Hb barely increased above the background levels within the dose range examined. The shapes of the dose response curves for total cysteinyl adducts (combined NPO and NPQ) in Hb and Alb were consistent with previous results of radiobinding experiments in naphthalene-dosed mice. Dose-specific levels of NPO-Alb remained essentially constant in mice over the dose range of 25-200 mg/kg b.w. while those of 1,2- and 1,4-NPQ-Alb diminished over this range. Comparing dose-specific levels of NPO-Alb in Swiss Webster mice with those published previously in F344 rats suggests that glutathione depletion in mice occurred at about 1/8th the administered dose previously observed in rats. This suggests that mice could be more susceptible than rats to the toxic effects of naphthalene due to more pronounced depletion of glutathione at a given dose.
萘对啮齿动物的毒性归因于其活性代谢产物萘-1,2-氧化物（NPO）、1,2-萘醌（1,2-NPQ）和1,4-萘醌（1,4-NPQ）。不同物种中这些活性代谢产物形成过程的差异有助于揭示萘发挥毒性的机制。蛋白质加合物使研究人员能够研究无法直接测量的活性代谢产物的分布情况。我们测定了经1.56 - 200mg萘/千克体重剂量处理的雄性瑞士韦伯斯特小鼠血液中血红蛋白（Hb）和白蛋白（Alb）中上述代谢产物的半胱氨酰加合物。NPO加合物（分别命名为NPO1-Hb、NPO2-Hb、NPO1-Alb和NPO2-Alb）的水平随给药剂量呈非线性增加；Alb加合物的水平高于Hb加合物的水平；NPO1加合物的水平高于NPO2加合物的水平。NPQ加合物（1,2-NPQ-Alb、1,4-NPQ-Alb、1,2-NPQ-Hb和1,4-NPQ-Hb）的水平低于NPO加合物。虽然高于12.5mg萘/千克体重剂量时NPQ-Alb有所增加，但在所研究的剂量范围内，NPQ-Hb的水平仅略高于背景水平。Hb和Alb中总半胱氨酰加合物（NPO和NPQ总和）的剂量反应曲线形状与之前萘处理小鼠的放射结合实验结果一致。在25 - 200mg/千克体重的剂量范围内，小鼠体内NPO-Alb的剂量特异性水平基本保持恒定，而1,2-和1,4-NPQ-Alb的水平在此范围内降低。将瑞士韦伯斯特小鼠中NPO-Alb的剂量特异性水平与之前在F344大鼠中公布的水平进行比较，结果表明小鼠体内谷胱甘肽耗竭时的给药剂量约为之前在大鼠中观察到的1/8。这表明在给定剂量下，由于于谷胱甘肽更明显的耗竭使得小鼠可能比大鼠对萘的毒性作用更敏感。
