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The Relationship Between Reactivity Of Metabolites Of Pyrrolizidine Alkaloids And Extrahepatic Toxicity, R. A. Cooper, R. J. Huxtable
The Relationship Between Reactivity Of Metabolites Of Pyrrolizidine Alkaloids And Extrahepatic Toxicity, R. A. Cooper, R. J. Huxtable
Roland A. Cooper
Pyrrolizidine alkaloids (PAs) are a large group of structurally similar toxins. In animals, including man, they are hepatotoxic and in some cases pneumo- and neurotoxic. PAs are metabolized by the liver P450 system to reactive dehydroalkaloid (DHA) intermediates. PA toxicity is a result of alkylation of macromolecules by DHAs. We have measured the relative reactivity of a series of semi-synthetic DHAs by recording the rate at which they alkylate a model nucleophile, 4-(p-nitrobenzyl)pyridine. Rate data fit mono- or biexponential equations. Rank order of reactivity for the macrocyclic and open ester DHAs was the same as those measured for DHA hydrolysis. …