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 r ight ventricular hypertrophy. The release of the highly reactive, alky lating pyrrole, dehydromonocrotaline, from the isolated rat liver perf used with monocrotaline has now been demonstrated and quantified, usin g thiopropyl Sepharose resin as a trapping agent. The isolated liver e xtracted 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 ex creted into bile and 7.6% was detectable as pyrrolic metabolites. Of t hese metabolites, 156 nmol/g liver appeared in the bile as glutathiony ldehydroretronecine, with the average concentration in bile being 3.53 mM. The perfusion medium at the end of the perfusion contained 113 nm ol/g liver of the two pyrroles, dehydroretronecine and glutathionyldeh ydroretronecine. Remaining in the liver was 56 nmol/g of tissue-bound pyrroles. Over the course of a l-hr perfusion, 88 nmol/g liver of dehy dromonocrotaline was released into the perfusate, as determined by tra pping with thiopropyl Sepharose, a resin that reacts only with alkylat ing pyrroles. This establishes that dehydromonocrotaline is released o n perfusing the isolated liver with monocrotaline. The amount released under these conditions is equivalent to 1.08 +/- 0.06 mg/kg body weig ht, which can be compared to the intravenous dose of 4.85 mg/kg body w eight of dehydromonocrotaline found by others to be a pneumotoxic dose . (C) 1994 Academic Press, Inc.