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

缺氧和常氧条件下药物和其他制剂的生物活化机制

• 批准号: 3877458
• 负责人: BRIAN R SMITH
• 金额: --
• 依托单位: UNIVERSITY OF NEW MEXICO
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3877458
• 关键词: alkylation; drug adverse effect; drug design /synthesis /production; electron transport; hypoxia; image enhancement; imidazole; laboratory rat; mevalonate; nuclear magnetic resonance spectroscopy; oxidation reduction reaction

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.

已知许多化学物质会发生生物转化反应 这导致有毒衍生物的形成。 在某些情况下， 这些化学品是工业或环境化学品。 换句 在某些情况下，它们是药物，有毒代谢物有时被 导致药物出现不良副作用。 我们 研究集中在药物的还原性生物活化上， 其他化学品。 这种类型的生物转化是促进 通过但不限于组织氧 水平低于正常水平。 我们研究了两组 已知进行还原生物转化反应的化学物质： 硝基取代的咪唑类化合物， 实验辐射敏化剂（也会引起外周 神经病变作为副作用，可能是由于还原生成 灭火器（包括灭火剂）， 卤代一碳和二碳烷烃。 哈龙被广泛使用 作为灭火剂，并被怀疑 类似于已知发生的还原脱卤反应 四氯化碳。 硝基咪唑衍生物正在合成， 作为有效的辐射增敏剂，但仍应 有效的辐射增敏剂。 这将通过 咪唑环上的阻断位置，我们已经证明， 通过硝基还原转化为亲电中心， 取代基 将对大鼠施用哈龙制剂，然后进行检查 动物组织的过氧化变化的证据， 通过卤化碳的还原脱卤。 烷烃呼出 也将被定量为 哈龙引起的脂质过氧化。 可能促进的条件 还可以探索还原代谢。 这些条件 包括老鼠在大气中接触哈龙， 耗尽氧气，或在低浓度污染的大气中 一氧化碳