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. The reaction with 4-(p-nitrobenzyl)pyridine was easier to follow, however, as rates of reaction can easily be controlled by temperature or level of acid catalysis, and the final product can be measured colorimetrically. DHAs of the primarily hepatotoxic alkaloids, retrorsine and seneciphylline, were more reactive than DHAs of monocrotaline and trichodesmine, which additionally produce pneumo- and neurotoxicity, respectively. This suggests that DHAs with greater stability (longer half-lives) are able to survive long enough to reach target organs downstream form the liver. We believe that differences in PA metabolism and the nature of toxicity ultimately produced are in part related to differences in reactivity of the primary toxic intermediate, the DHA.
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