QUINONE METHIDE TOXICITY

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Most xenobiotics must be metabolized to exert their toxic or carcinogenic effects. Pan research has focused on the formation of reactive electrophilic intermediates as mediators of these deleterious processes. Two widely studied classes of reactive intermediates are quinones and quinoneimines. A structurally related class of chemical intermediates, quinone methides, has received surprisingly little attention. Phenolic compounds with ortho or para alkyl groups are capable of forming quinone methides. This includes a large number of chemicals present in foods and medicines. It is our hypothesis that the toxicity of certain phenolic compounds can be explained, in part, by their metabolism to reactive quinone methides, which in turn covalently bind to cellular macromolecules. Previous work has demonstrated that quinone methides are formed during xenobiotic metabolism of a limited number of phenolic compounds, but data showing a causal linkage between quinone methide formation and toxicity is lacking. Butylated hydroxytoluene and eugenol are examples of phenolic compounds for which the formation of reactive quinone methide intermediates has been suggested to play a role in the hepatic and pulmonary toxicity of these compounds. This proposal seeks to measure and quantify the amount of quinone methides formed during the oxidative metabolism of butylated hydroxytoluene, eugenol and related phenols and to link the formation of these reactive intermediates to toxicity. seen in isolated liver cells or tissue slices from liver or lung. Analogs of these compounds which cannot form quinone methide metabolites will be used to assess the role of other possible mechanisms of toxicity. In addition, stable quinone methides from these compounds will be tested directly on cells and tissue slices for their possible cytotoxic effects and mechanism of toxicity.