THE RELATIONSHIP BETWEEN THE CONCENTRATION OF THE PYRROLIZIDINE ALKALOID MONOCROTALINE AND THE PATTERN OF METABOLITES RELEASED FROM THE ISOLATED LIVER

Hepatic metabolism of the pyrrolizidine alkaloid monocrotaline results in extrahepatic toxicity caused by the release of metabolites from th e liver. We have quantified the release of pyrrolic metabolites into t he perfusate and bile of isolated rat livers perfused with monocrotali ne over the concentration range of 0.125-1.5 mM. Over a l-hr perfusion period, the amount of dehydromonocrotaline released from the liver va ried from 60 nmol/g liver at 0.125 mM monocrotaline to 460 nmol/g live r at 1.5 mM monocrotaline. As a percentage of total pyrrole release, t his is a monotonic increase from 30 to 41%. The percentage of pyrroles released into the bile, representing mainly 7-glutathionyl-6,7-dihydr o-1-hydroxymethyl-5H-p (GSDHP), increased over the monocrotaline conce ntration range 0.125-1.0 mM, but fell sharply from 38% of total at the latter concentration to 21% of total at 1.5 mM monocrotaline. This is probably a reflection of glutathione depletion. Nonalkylating pyrrole released into the perfusate, represents largely 7-dihydro-7-hydroxy-1 -hydroxymethyl-5H-pyrrolizine (DHP). Pyrrole released into perfusate s howed an opposite pattern. The percentage of pyrroles released as DHP into the perfusate fell from 38% at 125 mM monocrotaline to 27% at 1.0 mM monocrotaline, but increased sharply to 38% at 1.5 mM monocrotalin e. When calculated on a body weight basis, concentrations of monocrota line of 500 mu M result in the release from the liver of 5.3 mu mol/kg of dehydromonocrotaline. This is comparable to the amount of dehydrom onocrotaline, given in vivo, required for pneumotoxicity. The amounts of other pyrrolic metabolites released over a I-hr period of perfusion are insufficient to produce pneumotoxicity in vivo. Based on the body weight of the donor rat, pyrrole release on perfusion of the isolated liver with 1500 mu M monocrotaline can be calculated as mu mol/kg bod y weight. These amounts can then be compared to acute doses producing pneumotoxicity in vivo (given in parentheses): DHP, 13 mu mol/kg body weight released (350 mu mol/kg); GSDHP, 8 mu mol/kg (300 mu mol/kg); a nd dehydromonocrotaline, 14 mu mol/kg (15 mu mol/ kg). This suggests, therefore, that dehydromonocrotaline is the pyrrolic metabolite contri buting the most to the extrahepatic toxicity of monocrotaline. (C) 199 5 Academic Press, Inc.