Pyrrolizidine alkaloids: Physicochemical correlates of metabolism and toxicity

Pyrrolizidine alkaloids occur in the Leguminosae, Asteraceae and Boraginaceae families. Toxicity is dependent on hepatic oxidation by cytochrome P450 to reactive pyrrolic dehydroalkaloids (DHAs). These alkylate nucleophilic sites on cell metabolites and macromolecules. DHAs undergo hydrolysis at rates ranging from 2.2 sec(-1) to 0.1 sec(-1) (i.e. with half-lives ranging from 0.3 sec to 5.3 sec). Both the site of toxicity (liver, lung, central nervous system, etc.) and degree of toxicity (lethality or LD50) are related to the pattern of metabolism. This pattern, in turn, is related to the rate of hydrolysis. This is greater for DHAs having acyclic esters than for cyclic diester DHAs. The rate also appears to be greater for cyclic diester DHAs with smaller substituents at the C14 position. We postulate that the rate of hydrolysis of a given DHA and hence the degree and kind of toxicity expressed by the parent PA is strongly dependent on steric hindrance at the C7 ester linkage.