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 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.
Yan
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CC
Department of Pharmacology, College of Medicine, University of Arizona, Tucson 85724.
Huxtable
R J
RJ
D000704:Analysis of Variance; D000818:Animals; D001646:Bile / Q000187:drug effects / Q000378:metabolism; D002273:Carcinogens / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005978:Glutathione / Q000031:analogs & derivatives / Q000378:metabolism; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D013058:Mass Spectrometry; D016686:Monocrotaline / Q000031:analogs & derivatives / Q000378:metabolism / Q000633:toxicity*; D010477:Perfusion; D011758:Pyrroles / Q000378:metabolism*; D051381:Rats
C091658:7-glutathionyl-6,7-dihydro-1-hydroxymethyl-5H-pyrrolizine; D002273:Carcinogens; D011758:Pyrroles; C014114:monocrotaline pyrrole; D016686:Monocrotaline; D005978:Glutathione; C007241:dehydroretronecine