MECHANISMS OF BIOACTIVATION OF DRUGS AND OTHER AGENTS UNDER HYPOXIA AND NORMOXIA

已知许多化学物质会发生生物转化反应。 这会导致有毒衍生品的形成。在某些情况下， 这些化学品是工业或环境化学品。在其他 它们是毒品，有毒的代谢物有时是 对药物的不良副作用负责。我们的 研究的重点是药物的还原生物活性和 其他化学品。这种类型的生物转化是便利的 通过，但不限于，组织氧气 水平低于正常水平。我们一直在研究两组 已知会发生还原生物转化反应的化学物质： 硝基取代咪唑类化合物的临床应用 实验性辐射增敏剂(也会导致外周 神经病变是一种副作用，可能是由于还原生成 代谢物)和哈龙灭火器 卤化的一个和两个碳烷烃。哈龙被广泛使用 作为灭火器代理商，并怀疑经历了 还原脱卤化反应与已知发生的反应相似 用四氯化碳。 硝基-咪唑类化合物正在被合成，它们应该起作用 作为有效的辐射敏感剂，但它仍然应该是 有效的辐射敏感剂。这将通过以下方式实现 咪唑环上的封闭位置，我们已经证明了 通过还原硝基转移到亲电中心 取代基。 将给老鼠注射哈龙剂，然后进行检查 从动物组织中寻找过氧化改变的证据 通过对卤代烃的还原脱卤化。烷烃的呼出 被暴露的动物也将被量化为一个指数 哈龙引起的脂质过氧化。可能便利的条件 还可以探索还原新陈代谢。这些条件 包括使大鼠部分暴露于大气中哈龙 耗尽氧气，或在被低水平污染的大气中 一氧化碳。

Many chemicals are known to undergo biotransformation reactions which result in the formation of toxic derivatives. In some cases, these chemicals are industrial or environment chemicals. In other cases they are drugs, with the toxic metabolites sometimes being responsible for undesirable side effects of the drug. Our investigations are focused on reductive bioactivation of drugs and other chemicals. This type of biotransformation is facilitated by, but not restricted to, conditions where the tissue oxygen levels are below normal. We have been studying two groups of chemicals known to undergo reductive biotransformation reactions: Nitro-substituted imidazole compounds used clinically as experimental radiation sensitizers (which also cause peripheral neuropathy as a side effect, possible due to reductively generated metabolites), and Halon fire extinguishers which are fully halogenated one and two carbon alkanes. Halons are used widely as fire extinguisher agents, and are suspected to undergo reductive dehalogenation reactions similar those known to occur with carbon tetrachloride. Nitro-imidazole derivatives are being synthesized which should act as effective radiation sensitizers, but which should still be effective radiation sensitizers. This will be accomplished by blocking positions on the imidazole ring which we have shown to be converted to electrophilic centers by reduction of the nitro- substituent. Halon agents will be administered to rats, followed by examination of the animals tissues for evidence of peroxidative changes caused by reductive dehalogenation of halocarbons. Exhalation of alkanes by the exposed animals will also be quantitated as an index of Halon-induced lipid peroxidation. Conditions likely to facilitate reductive metabolism may also be explored. These conditions include exposure of rats to Halons in atmospheres partially depleted of oxygen, or in atmospheres contaminated with low levels of carbon monoxide.