Quantitation of the hepatic release of metabolites of the pyrrolizidine alkaloid, monocrotaline.

Pyrrolizidine alkaloids such as monocrotaline are bioactivated in the liver to pneumotoxins that cause pulmonary arterial hypertension and right ventricular hypertrophy. The release of the highly reactive, alkylating pyrrole, dehydromonocrotaline, from the isolated rat liver perfused with monocrotaline has now been demonstrated and quantified, using thiopropyl Sepharose resin as a trapping agent. The isolated liver extracted 55% of the alkaloid over the course of a 1-hr perfusion with 0.5 mM monocrotaline. Of the total monocrotaline perfused, 0.4% was excreted into bile and 7.6% was detectable as pyrrolic metabolites. Of these metabolites, 156 nmol/g liver appeared in the bile as glutathionyldehydroretronecine, with the average concentration in bile being 3.53 mM. The perfusion medium at the end of the perfusion contained 113 nmol/g liver of the two pyrroles, dehydroretronecine and glutathionyldehydroretronecine. Remaining in the liver was 56 nmol/g of tissue-bound pyrroles. Over the course of a 1-hr perfusion, 88 nmol/g liver of dehydromonocrotaline was released into the perfusate, as determined by trapping with thiopropyl Sepharose, a resin that reacts only with alkylating pyrroles. This establishes that dehydromonocrotaline is released on perfusing the isolated liver with monocrotaline. The amount released under these conditions is equivalent to 1.08 +/- 0.06 mg/kg body weight, which can be compared to the intravenous dose of 4.85 mg/kg body weight of dehydromonocrotaline found by others to be a pneumotoxic dose.