title: Relation of structural features to pyrrolic metabolites in livers of rats given pyrrolizidine alkaloids and derivatives.
abstract: Levels of pyrrolic metabolites have been measured in the livers of rats given some pyrrolizidine alkaloids and semisynthetic derivatives. Structural and chemical features favouring the formation of such metabolites have been defined. The most important of these were: steric hindrance or chemical properties giving resistance to ester hydrolysis; lipophilic character, allowing access to hepatic microsomal enzymes; a conformation favoring microsomal oxidation of the pyrroline ring in preference to N-oxidation. In addition, the presence of ester groups gave the resulting pyrroles high chemical reactivity, leading to tissue binding. Amounts of pyrroles bound to liver were very low when animals were given either highly water soluble pyrrolizidine derivatives, including non-esterified bases or more-lipophilic esters if these were easily hydrolysed. Compounds prone to hydrolysis gave increased pyrrole levels in rats pretreated to deplete their esterase activity. Whereas heliotridine-based alkaloids usually give more pyrrole than similar retronecine esters, heliotridine ditiglate gave less pyrrole than retronecine ditiglate because the former was more open to hydrolytic attack. Among the carboxylic diesters, the cyclic retronecine diesters, in which the pyrrolizidine nucleus is more exposed to oxidative metabolism, gave the highest pyrrole levels in rats. Liver pyrrole measurements are useful for studying relationships between molecular structure, metabolism and toxicity of pyrrolizidine derivatives. They can be used for screening alkaloids for potential toxicity and for assessing dose levels suitable for toxicity tests when limited material is available.
mesh_terms: D000818:Animals; D001711:Biotransformation; D004952:Esters / Q000378:metabolism; D008055:Lipids; D008099:Liver / Q000378:metabolism*; D008297:Male; D008968:Molecular Conformation; D011758:Pyrroles / Q000378:metabolism*; D011763:Pyrrolizidine Alkaloids / Q000378:metabolism*; D051381:Rats; D012995:Solubility; D013329:Structure-Activity Relationship
chemical_list: D004952:Esters; D008055:Lipids; D011758:Pyrroles; D011763:Pyrrolizidine Alkaloids