再访广岛
【德】麦考·帕默 著
郎伦友 译
第七章 第二节
7.2 作用的形式和毒代谢动力学
图7.1显示了硫芥子气和路易斯毒气的分子结构,显然它们相当不同;特别是硫芥子气的两个氯乙基,这是路易斯毒气中所缺少的能促成其与DNA反应的物质。(详见下文)这说明尽管结果相似,但它们与细胞内的分子的反应却是不同的。
7.2.1 同DNA的反应
硫芥子气与DNA的反应首先是形成一个环硫离子(见图7.2)。这个三元环是高度不稳定的,可以同细胞内的任何亲核体发生反应;但是由于某些原因,比如电离辐射(见2.1一节),最重要的目标分子是DNA。在DNA中发现的四种碱基(脚注2)都可以发生反应,但最活跃的反应物是鸟嘌呤,特别是在该图所示的咪唑环中特有的氮(N7)。重要的是,硫芥子气是一个二价的分子,与中心的硫原子连接的两个氯乙基( -CH? - CH? -Cl)都可以以相同的方式反应。这就可能导致位于DNA分子相对链条上的两个碱基之间的交叉连接;随着这种交叉连接而产生的是两股链条都有可能断裂,(脚注3)结果是用电离辐射也能观察到同样类型的损伤。在硫芥子气的生物效应方面,这样的交叉连接的一个重要作用是由早期的发现支持的,缺少两个反应基的任何一个,类似的化合物的毒性要低很多。【107,第35页】
图7.2 被硫芥子气交叉连接的DNA鸟嘌呤碱
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Cl:氯;S:硫;N:氮;O:氧;NH?:胺基;OH:羟基。
dR代表脱氧核糖。第一步是形成一个环硫离子;这个三元环是高度不稳定的,容易受到N7或其他亲核物质如谷胱甘肽的攻击。第二个鸟嘌呤俘获的步骤与第一个鸟嘌呤俘获的步骤相同。
电离辐射与硫芥子气引起的致突变DNA损伤的相似性说明,两种有毒物质在短期内都会产生相似的生物效应,诸如骨髓损伤,而从长期看则可能有白血病和癌症。令人惊异的是,路易斯毒气对DNA的反应性很少受到关注;然而与硫芥子气不同,路易斯毒气没有确切的致突变或致癌潜力的记录。【21,109】在广岛和长崎轰炸的幸存者中,白血病和某些实体瘤的发病率显著增加,【110,111】这进一步支持了用在摧毁这两座城市的是硫芥子气,而不是路易斯毒气。
7.2.2 谷胱甘肽的耗竭
在低浓度的硫芥子气中,与DNA的反应导致了大部分损伤,而与其他亲核试剂的反应则在更高的水平上提供了另一种毒性机制。谷胱甘肽是一种特别重要的分子,它在清除细胞内部多种有毒化合物中担当关键的角色。如果谷胱甘肽由于与硫芥子气反应而消耗殆尽,将损害细胞的中和活性氧化物(ROS)的能力。活性氧化物是许多代谢过程的主要产物或副产物;得不到保护的活性氧化物可能会导致细胞毒性效应。【112】
一个涉及活性氧物的生化途径是皮肤色素(黑色素)的形成;实行这一途径的黑色素细胞比角质形成细胞(非色素细胞【113】)更容易受到硫芥子气毒性的影响。能杀死黑色素细胞但允许角质形成细胞再生的暴露程度可能导致皮肤脱色。另一方面,低水平的硫芥子气允许角质形成细胞和黑色素细胞都再生则可能导致皮肤色素沉着。后一种情况通常被看作是对脱色的描述。
谷胱甘肽通过它的巯基(-SH)与硫芥子气反应,这个巯基是一种极好的亲核剂,用于攻击图7.2 所示的环硫醚中间体。尽管化学反应不同,但巯基也与路易斯毒气发生剧烈反应;这表明早期皮肤上和粘膜上的症状的相似性的确是由这个机制促成的。然而关于路易斯毒气在生物体内进行反应的实验数据非常稀少。【21,109】
7.2.3 系统的吸收和分配
硫芥子气是通过皮肤接触、吸入和摄入被吸收的。第一次世界大战期间,暴露于硫芥子气中的士兵,还有工厂中生产这种毒气的工人,通常是用防毒面具进行保护的;相比之下,广岛和长崎那些没有得到保护的不知情的受害者很有可能就是通过这三条渠道摄入大量毒气的。
在对实验动物的皮肤进行实验性应用时,80%的化合物通常会蒸发掉,其余20%将被吸收。而被吸收的部分有大约80%,即总量的16%真正进入了血液循环,然后进入内脏器官;其余的部分(总量的4%)在皮肤中发生反应,并存留下来。【114】进入系统的部分分散到不同的器官中。不同器官里发现的相对丰度在不同的研究中有所不同,这些研究采用的是不同的检测方法——化学的【115】、放射性示踪剂【116,117】、或DNA损伤【1168——显然具有强大的血液流动的器官接收和保留的数量最高。这些器官有大脑、肺脏、脾脏和肾脏。
如前所述,硫芥子气水溶性很差;这样的物质是疏水性的或亲脂性的,它们容易积聚在脂质(脂肪样的物质)中。大脑不仅有很强的灌注能力,而且富含髓鞘形式的脂类。髓鞘包裹着众多的神经纤维,起着电绝缘体的作用。因此可以理解,DNA丰度最高的器官是大脑,【118】略高于肺脏。然而由于大脑细胞的增殖通常非常缓慢,这个器官对于硫芥子气造成的DNA损伤结果不是十分敏感,与它对辐射的低敏感性相似。
随着时间的推移,硫芥子气将从大脑和其他器官重新分配到脂肪含量最高的组织中。这是由德拉希等人【115】论证的,他们检验了一个在接触硫芥子气一个星期后死于硫芥子气中毒的伊朗士兵的尸体。值得注意的是,在此之后观察到的硫芥子气仍然以它原有的未发生反应的形式存在。随着时间的推移,脂肪组织通过血液缓慢地重新分布到其他器官,这可能会导致DNA和细胞损伤的持续。这也可能有助于已知的硫芥子气受害者缓慢恢复,还有可能有助于广岛和长崎的患者“辐射病”的延迟发作。(见8.8一节)
岳等人【119】在实验室中将大老鼠暴露于硫芥子气后,对其几个主要器官中的DNA加合物的丰度进行了比较。当把每个组织中的DNA总量进行标准化后,发现骨髓中的含量最高,接下来依次是大脑、胰腺、肺脏和脾脏。骨髓对硫芥子气的敏感性是长久以来认定的事实,【120】性腺也是如此。综上所述,我们注意到报告的一些器官中的高水平是一致的——大脑、肺脏和肾脏——它们都属于最不容易受电离辐射的器官。
7.2.4 新陈代谢
硫芥子气的反应性质使其容易受代谢转化和失活等多种途径的影响。我们已经讨论过它同谷胱甘肽的反应;这个反应 是由谷胱甘肽-硫-转移酶促进的,这种转移酶在肝脏和小肠的上皮细胞中含量特别丰富。谷胱甘肽的结合作用是一种解除药物和外源性药物毒性的有效途径;只要谷胱甘肽没有被大量的底物——例如皮肤中的硫芥子气耗尽 ,这种反应就是有好处的。
硫芥子气也是可以水解的,水解的过程分为两步,结果是它的灭活:(脚注4)
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)
Cl:氯;CH2:甲烯;S:硫;H?O:水;OH:羟基;HCl:氯化氢。
图7.3 硫芥子气的氧化代谢。
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Sulfur mustard(SM):硫芥子气;SM sulfoxide:硫芥亚砜;SM sulfone:硫芥砜;divinyl sulfone:二乙烯基砜。 O:氧;NH:胺;NH2:氨基。
硫原子可以被氧化,最有可能的是被过氧化物酶或单加氧酶氧化。首先生成亚砜,然后生成砜;砜可以消除氯化氢生成二乙烯基砜。二乙烯基砜与天然硫芥子气一样具有两个反应基团,具有诱变性。
另一个重要的反应是在生物体内普遍发生的氧化。【121】作为原因的酶显然还没有被鉴定出来;在这样的证据获得之前,细胞色素P450和过氧化物酶都是可能的候选酶。第一次氧化的中间物是亚砜,它具有低毒的活性(见图7.3);然而第二次氧化将生成砜,它能够消除氯化氢并由此转化成二乙烯基砜,二乙烯基砜具有高反应性和诱变性。【122】关于这一点,值得注意的是,甲状腺中存在高水平的过氧化物酶。已知甲状腺中的过氧化物酶介导结构相似的硫醚化合物的硫氧化,【123】甲状腺中硫芥子气转化为二乙烯基砜有可能使该器官的致癌活性增加。甲状腺癌已经在伊朗硫芥子气受害者身上观察到了,【124】甲状腺癌的发病率在广岛和长崎的幸存者中也显著增加。【125】
【脚注】
2:这些碱基有嘌呤衍生物腺嘌呤和鸟嘌呤以及嘧啶衍生物胞嘧啶和胸腺嘧啶。在DNA中,胸腺嘧啶由尿嘧啶取代。
3:这种情况已经用氮芥子气【52】演示过,氮芥子气以硫芥子气同样的方式与DNA发生反应。
4:在自然环境中也会发生水解;然而由于硫芥子气水溶性差,这个过程将会很慢。
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