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

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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.