Brambilla G, Robbiano L, Cajelli E, Martelli A, Turmolini F, Mazzei M
Institute of Pharmacology, University of Genoa, Italy.
J Pharmacol Exp Ther. 1988 Mar;244(3):1011-5.
In conditions similar to those occurring in the stomach, the sympathomimetic drug dimethophrine was found to react with nitrite yielding 2,6-dimethoxy-1,4-benzoquinone (DMBQ). The in vitro and in vivo studies carried out to evaluate the capability of DMBQ to produce cytotoxic and genotoxic effects provided the following results. A dose-related reduction of V79 cells plating efficiency was observed for DMBQ concentrations ranging from 10 to 80 microM; a similar reduction in the fraction of viable cells excluding trypan blue occurred after exposure to 4-fold higher concentrations. A dose-dependent amount of DNA fragmentation was revealed by the alkaline elution technique either in V79 cells exposed to DMBQ concentrations ranging from 10 to 80 microM or in kidney, gastric mucosa and brain of rats treated with single p.o. doses ranging from 33 to 300 mg/kg. Both in vitro and in vivo DNA lesions were largely repaired within 24 hr, but their promutagenic character was demonstrated by the induction of 6-thioguanine-resistance in V79 cells. Primary cultures of rat hepatocytes displayed a greater resistance to the cytotoxic and DNA-damaging activities of DMBQ, and did not exhibit a clear evidence of DNA repair synthesis. Similarly, DNA fragmentation was practically undetectable in the rat liver. Therefore, DMBQ should be considered as a direct-acting genotoxic chemical which is metabolized to less, or nonreactive, species. These findings suggest that DMBQ could produce genotoxic effects in patients taking dimethophrine.
在与胃部情况相似的条件下，发现拟交感神经药物二甲福林与亚硝酸盐反应生成2,6 - 二甲氧基 - 1,4 - 苯醌（DMBQ）。为评估DMBQ产生细胞毒性和基因毒性作用的能力而进行的体外和体内研究得出了以下结果。对于浓度范围为10至80微摩尔的DMBQ，观察到V79细胞接种效率呈剂量相关降低；暴露于高4倍浓度后，排除台盼蓝的活细胞比例也有类似降低。碱性洗脱技术显示，在暴露于浓度范围为10至80微摩尔DMBQ的V79细胞中，以及在用单次口服剂量范围为33至300毫克/千克处理的大鼠的肾脏、胃黏膜和脑中，均有剂量依赖性的DNA片段化现象。体外和体内的DNA损伤在24小时内大多得到修复，但其促诱变特性通过在V79细胞中诱导6 - 硫鸟嘌呤抗性得以证明。大鼠肝细胞原代培养物对DMBQ的细胞毒性和DNA损伤活性表现出更大的抗性，且未表现出明显的DNA修复合成证据。同样，在大鼠肝脏中几乎检测不到DNA片段化。因此，DMBQ应被视为一种直接作用的基因毒性化学物质，其代谢为活性较低或无活性的物质。这些发现表明，DMBQ可能会对服用二甲福林的患者产生基因毒性作用。
