McDonald T A, Yeowell-O'Connell K, Rappaport S M
Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill 27599-7400.
Cancer Res. 1994 Sep 15;54(18):4907-14.
Protein binding of hemoglobin (Hb) and bone marrow was used to compare in vivo reactions of 3 electrophilic metabolites of benzene, i.e., benzene oxide and 1,2- and 1,4-benzoquinone (1, 2-BQ and 1, 4-BQ), in F344 rats and B6C3F1 mice. Following a single p.o. administration of a mixture of [14C]- and [13C6]benzene between 50 and 400 mg/kg body weight, cysteine adducts of benzene oxide, 1,2-BQ, and 1,4-BQ were assayed, and the proportions of cysteine-bound adducts to total protein binding were estimated. Although dose-related production of each adduct was seen, large differences were observed between species and tissues. With rat Hb, benzene oxide adducts represented 27% of the total Hb binding and 73% of the cysteinyl binding, whereas quinone adducts represented relatively small proportions. However, with mouse Hb, the 1,4-BQ adducts accounted for 5.5% of the total Hb binding and 12.2% of the cysteinyl binding, while 1,2-BQ and benzene oxide each accounted for less than 3% of the total. In the bone marrow of both rats and mice, BQ adducts were more abundant than those of benzene oxide. However, adducts of 1,2-BQ predominated in rat marrow (9% of binding), whereas adducts of 1,4-BQ were more abundant in the mouse (21% of binding). The average blood concentrations of 1,4-BQ were estimated from the adduct levels and reaction-rate constants to be 2-5-fold higher in the mouse than in the rat. This work suggests that BQ binding is favored over that of benzene oxide in the bone marrow; however, high background levels of BQ adducts, observed with Hb and bone marrow proteins, suggest that any toxic effects of the quinones should only arise from high exposures to benzene.
利用血红蛋白（Hb）和骨髓的蛋白质结合来比较苯的3种亲电代谢产物，即氧化苯以及1,2 - 苯醌和1,4 - 苯醌（1,2 - BQ和1,4 - BQ）在F344大鼠和B6C3F1小鼠体内的反应。在以50至400mg/kg体重单次口服给予[14C] - 和[13C6]苯的混合物后，检测氧化苯、1,2 - BQ和1,4 - BQ的半胱氨酸加合物，并估算半胱氨酸结合加合物占总蛋白质结合的比例。虽然观察到每种加合物的产生与剂量相关，但在物种和组织之间观察到了很大差异。对于大鼠血红蛋白，氧化苯加合物占总血红蛋白结合的27%，占半胱氨酸结合的73%，而醌加合物所占比例相对较小。然而，对于小鼠血红蛋白，1,4 - BQ加合物占总血红蛋白结合的5.5%，占半胱氨酸结合的12.2%，而1,2 - BQ和氧化苯各自占总量的比例均小于3%。在大鼠和小鼠的骨髓中，苯醌加合物比氧化苯加合物更丰富。然而，1,2 - BQ加合物在大鼠骨髓中占主导（占结合的9%），而1,4 - BQ加合物在小鼠中更丰富（占结合的21%）。根据加合物水平和反应速率常数估算，小鼠体内1,4 - BQ的平均血药浓度比大鼠高2至5倍。这项研究表明，在骨髓中苯醌结合比氧化苯结合更受青睐；然而，在血红蛋白和骨髓蛋白中观察到的苯醌加合物的高背景水平表明，醌类的任何毒性作用应该仅源于高剂量接触苯。
