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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. …

We report a simple and rapid procedure for estimating the aqueous half-lives of the reactive metabolites of pyrrolizidine alkaloids that are responsible for toxicity. The metabolites (dehydroalkaloids; DHAs) were rapidly added to a 0.5 mM HEPES solution, pH 8.0. The subsequent fall in pH, due to ester hydrolysis, was followed potentiometrically. The change in pH was well described by single-component exponential decay, allowing the derivation of rate constants and half-lives of hydrolysis. Half-lives varied from 0.31 sec for dehydro-7-acetyllycopsamine to 5.36 sec for dehydrotrichodesmine. The results support the view that alkaloids whose DHA metabolites have longer half-lives produce greater extrahepatic …

Monocrotaline and trichodesmine are structurally closely related pyrrolizidine alkaloids (PAs) exhibiting different extrahepatic toxicities, trichodesmine being neurotoxic (LD(50) 57 mu mol/kg) and monocrotaline pneumotoxic (LD(50) 335 mu mol/kg). We have compared certain physicochemical properties and metabolic activities of these two PAs in order to understand the quantitative and qualitative differences in toxicity. Both PAs were metabolized in the isolated, perfused rat liver to highly reactive pyrrolic dehydroalkaloids that appear to be responsible for the toxicity of PAs. More dehydrotrichodesmine (468 nmol/g liver) than dehydromonocrotaline (116 nmol/g liver) was released from liver into perfusate on perfusion for 1 hr with 0.5 …

Caissarone, a sea anemone iminopurine, produced an increase in the twitch response of the electrically stimulated guinea-pig ileum-myenteric plexus. In the same assay, caissarone reduced the inhibitory response to the endogenous neuromodulator, adenosine, the A1 adenosine receptor agonist, R-phenylisopropyladenosine (R-PIA), and the A2 agonist, 5'-(N-cyclopropyl)-carboxamidoadenosine (CPCA) in a dose-dependent manner. Schild plot analysis of antagonism by caissarone yielded slopes of near unity, indicating that caissarone acts as a simple competitive antagonist at the adenosine receptor. The dissociation constants (KB) for caissarone ranged from 0.53 mM to 0.78 mM. In functional nicotinic receptor assays in two human cell lines, caissarone failed …