Kawabata T T, White K L
Cancer Res. 1987 May 1;47(9):2317-22.
Several investigators have demonstrated that the humoral immune response of mice and splenocyte cultures was suppressed with benzo(a)pyrene [B(a)P] exposure. The mechanism of the B(a)P immunosuppression, however, has not been established. Since reactive metabolites of B(a)P, rather than the parent compound, have been shown to mediate the carcinogenic effects of B(a)P, it was hypothesized that the immunosuppression produced by B(a)P may also be mediated by its reactive metabolites. The objective of this investigation was to examine the role of B(a)P metabolism in the B(a)P-induced suppression of the in vitro humoral immune response. This was addressed by first determining if various B(a)P metabolites are capable of inhibiting the generation of antibody-forming cells (AFC) of splenocyte cultures. Addition of B(a)P or B(a)P-7,8-diol (2 X 10(-5) M) to splenocyte cultures produced a similar dose-dependent suppression of the in vitro T-dependent AFC response to sheep red blood cells. In contrast, decreases in the AFC response and cell viability of cultures exposed to the 4,5-diol or 9,10-diol were only observed at 2 X 10(-5) M. Exposure of cultures to 3-hydroxy-B(a)P resulted in a significant decrease in the AFC response at 2 X 10(-6) and 2 X 10(-5) M. Slight decreases in the AFC response were observed with the addition of B(a)P-4,5-epoxide or B(a)P-6,12-dione at 2 X 10(-6) M, whereas a dramatic decrease in the AFC response, as well as a 45% decrease in cell viability, was obtained at 2 X 10(-5) M. The second objective was to examine the effects of the cytochrome P-450 inhibitor, alpha-naphthoflavone (ANF), on the B(a)P- and B(a)P-7,8-diol-induced suppression of the in vitro AFC response. Exposure of splenocyte cultures to 2 X 10(-5) M ANF did not affect the AFC response. Coincubation of splenocytes with ANF was observed to attenuate the suppressive effects of B(a)P and B(a)P-7,8-diol. This concentration of ANF was observed to inhibit the metabolism of [3H]B(a)P by splenocyte cultures to water soluble metabolites. Moreover, B(a)P metabolism by splenic microsomal preparations of untreated mice was inhibited by ANF. These findings suggest that the B(a)P-induced suppression of the in vitro AFC response is mediated by B(a)P metabolites generated by cytochrome P-450 present within splenocytes.
几位研究人员已证明，苯并(a)芘[B(a)P]暴露会抑制小鼠和脾细胞培养物的体液免疫反应。然而，B(a)P免疫抑制的机制尚未明确。由于已表明B(a)P的活性代谢产物而非母体化合物介导了B(a)P的致癌作用，因此推测B(a)P产生的免疫抑制作用也可能由其活性代谢产物介导。本研究的目的是探讨B(a)P代谢在B(a)P诱导的体外体液免疫反应抑制中的作用。首先通过确定各种B(a)P代谢产物是否能够抑制脾细胞培养物中抗体形成细胞(AFC)的生成来解决这个问题。向脾细胞培养物中添加B(a)P或B(a)P - 7,8 - 二醇(2×10(-5)M)对体外针对绵羊红细胞的T细胞依赖性AFC反应产生了类似的剂量依赖性抑制。相比之下，仅在2×10(-5)M时观察到暴露于4,5 - 二醇或9,10 - 二醇的培养物中AFC反应和细胞活力的降低。将培养物暴露于3 - 羟基 - B(a)P在2×10(-6)和2×10(-5)M时导致AFC反应显著降低。添加B(a)P - 4,5 - 环氧化物或B(a)P - 6,12 - 二酮在2×10(-6)M时观察到AFC反应略有降低，而在2×10(-5)M时AFC反应急剧下降，同时细胞活力下降45%。第二个目的是研究细胞色素P - 450抑制剂α - 萘黄酮(ANF)对B(a)P和B(a)P - 7,8 - 二醇诱导的体外AFC反应抑制的影响。将脾细胞培养物暴露于2×10(-5)M ANF对AFC反应没有影响。观察到脾细胞与ANF共同孵育可减弱B(a)P和B(a)P - 7,8 - 二醇的抑制作用。该浓度的ANF被观察到抑制脾细胞培养物将[3H]B(a)P代谢为水溶性代谢产物。此外，未处理小鼠脾微粒体制剂的B(a)P代谢受到ANF的抑制。这些发现表明，B(a)P诱导的体外AFC反应抑制是由脾细胞内存在的细胞色素P - 450产生的B(a)P代谢产物介导的。
