Hepatic metabolism of the
pyrrolizidine alkaloid monocrotaline results in extrahepatic toxicity caused by the release of metabolites from the liver. We have quantified the release of pyrrolic metabolites into the perfusate and bile of isolated rat livers perfused with
monocrotaline over the concentration range of 0.125-1.5 mM. Over a 1-hr perfusion period, the amount of
dehydromonocrotaline released from the liver varied from 60 nmol/g liver at 0.125 mM
monocrotaline to 460 nmol/g liver at 1.5 mM
monocrotaline. As a percentage of total
pyrrole release, this is a monotonic increase from 30 to 41%. The percentage of
pyrroles released into the bile, representing mainly 7-glutathionyl-6,7-dihydro- 1-hydroxymethyl-5H-pyrrolizine (
GSDHP), increased over the
monocrotaline concentration 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
6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP).
Pyrrole released into perfusate showed an opposite pattern. The percentage of
pyrroles released as DHP into the perfusate fell from 38%
at 125 microM
monocrotaline to 27% at 1.0 mM
monocrotaline, but increased sharply to 38% at 1.5 mM
monocrotaline. When calculated on a
body weight basis, concentrations of
monocrotaline of 500 microM result in the release from the liver of 5.3 mumol/kg of
dehydromonocrotaline. This is comparable to the amount of
dehydromonocrotaline, given in vivo, required for pneumotoxicity. The amounts of other pyrrolic metabolites released over a 1-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 1,500 microM
monocrotaline can be calculated as mumol/kg
body weight. These amounts can then be compared to acute doses producing pneumotoxicity in vivo (given in parentheses): DHP, 13 mumol/kg
body weight released (350 mumol/kg);
GSDHP, 8 mumol/kg (300 mumol/kg); and
dehydromonocrotaline, 14 mumol/kg (15 mumol/kg). This suggests, therefore, that
dehydromonocrotaline is the pyrrolic metabolite contributing the most to the extrahepatic toxicity of
monocrotaline.