Kawabata T T, White K L
Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298.
J Toxicol Environ Health. 1990 May;30(1):53-67. doi: 10.1080/15287399009531409.
Naphthalene-induced pulmonary and renal toxicity and polycyclic aromatic hydrocarbon-induced carcinogenesis are known to be mediated by their reactive metabolites. Subchronic exposure (90 d) of mice to naphthalene does not alter humoral and cellular-mediated immune responses, whereas polycyclic aromatic hydrocarbons, such as benzo[a]pyrene and 7,12-dimethylbenzanthracene, are known to be immunosuppressive. To understand these differences, the antibody-forming cell (AFC) responses of splenocyte cultures exposed to naphthalene (2, 20, and 200 microM) were evaluated. At these concentrations, the antibody-forming cell response to sheep red blood cells (RBC) was not affected. To determine if reactive metabolites of naphthalene were immunosuppressive, splenocytes were exposed to naphthalene metabolites by direct addition or through the use of a metabolic activation system. The addition of 1-naphthol (70 and 200 microM) and 1,4-naphthoquinone (2, 7, and 20 microM) resulted in a decreased antibody-forming cell response. Suppression of AFC responses was also obtained by culturing splenocytes with liver S9 and naphthalene. Since splenic metabolism of naphthalene to nonimmunosuppressive metabolites may account for the absence of immunotoxicity, the types of naphthalene metabolites generated by splenic microsomes were determined. It was observed that splenic microsomes were unable to generate any detectable naphthalene metabolites, whereas liver microsomes were able to generate both 1,2-naphthalene diol and 1-naphthol. Thus, the absence of an immunosuppressive effect by naphthalene exposure may be related to the inability of splenocytes to metabolize naphthalene. Moreover, the concentration of naphthalene metabolites generated within the liver that may diffuse to the spleen may be inadequate to produce immunotoxicity.
已知萘诱导的肺和肾毒性以及多环芳烃诱导的致癌作用是由其活性代谢产物介导的。小鼠亚慢性暴露（90天）于萘不会改变体液免疫和细胞介导的免疫反应，而多环芳烃，如苯并[a]芘和7,12 - 二甲基苯并蒽，已知具有免疫抑制作用。为了解这些差异，评估了暴露于萘（2、20和200微摩尔）的脾细胞培养物的抗体形成细胞（AFC）反应。在这些浓度下，对绵羊红细胞（RBC）的抗体形成细胞反应未受影响。为了确定萘的活性代谢产物是否具有免疫抑制作用，脾细胞通过直接添加或使用代谢活化系统暴露于萘代谢产物。添加1 - 萘酚（70和200微摩尔）和1,4 - 萘醌（2、7和20微摩尔）导致抗体形成细胞反应降低。通过将脾细胞与肝脏S9和萘一起培养也获得了AFC反应的抑制。由于萘在脾脏中代谢为非免疫抑制性代谢产物可能解释了免疫毒性的缺乏，因此确定了脾微粒体产生的萘代谢产物类型。观察到脾微粒体无法产生任何可检测到的萘代谢产物，而肝微粒体能够产生1,2 - 萘二醇和1 - 萘酚。因此，萘暴露缺乏免疫抑制作用可能与脾细胞无法代谢萘有关。此外，肝脏中产生的可能扩散到脾脏的萘代谢产物浓度可能不足以产生免疫毒性。
