Abstract
The metabolism and distribution of 14C-monocrotaline in Fisher 344 (F344) rats was compared with that in Sprague-Dawley (SD) rats. In vitro microsomal preparations, in situ isolated perfused livers and in vivo excretion and distribution studies were used to discern any differences between these two strains. These strains have previously been shown to differ in their susceptibility to monocrotaline-induced pulmonary hypertension. Hepatic phase I metabolism appears to be similar in both strains with N- oxidation and dehydrogenation to the reactive pyrroles as the major pathways. During the liver perfusions, SD rats generated more monocrotalic acid than F344 rats, but the microsome and excretion studies demonstrated no significant differences in the amount of monocrotalic acid. Monocrotalic acid is a stable byproduct of dehydromonocrotaline reacting with cellular nucleophiles and indicates the amount of monocrotaline dehydrogenation when carboxylesterase activity is negligible. These data suggest that the differences in strain susceptibility to pulmonary vascular toxicity is most likely due to differences in their response to the toxic metabolites.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 115-123 |
| Number of pages | 9 |
| Journal | Comparative Biochemistry and Physiology - B Biochemistry and Molecular Biology |
| Volume | 117 |
| Issue number | 1 |
| DOIs | |
| State | Published - 1997 |
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Keywords
- Fisher 344
- liver perfusion
- metabolism
- monocrotalic acid
- monocrotaline
- pyrrolizidine alkaloid
- Sprague-Dawley
ASJC Scopus subject areas
- Biochemistry
- Physiology
Cite this
Monocrotaline metabolism and distribution in Fisher 344 and Sprague- Dawley rats. / Reid, M. J.; Lamé, M. W.; Morin, O.; Wilson, Dennis W; Segall, H. J.
In: Comparative Biochemistry and Physiology - B Biochemistry and Molecular Biology, Vol. 117, No. 1, 1997, p. 115-123.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Monocrotaline metabolism and distribution in Fisher 344 and Sprague- Dawley rats
AU - Reid, M. J.
AU - Lamé, M. W.
AU - Morin, O.
AU - Wilson, Dennis W
AU - Segall, H. J.
PY - 1997
Y1 - 1997
N2 - The metabolism and distribution of 14C-monocrotaline in Fisher 344 (F344) rats was compared with that in Sprague-Dawley (SD) rats. In vitro microsomal preparations, in situ isolated perfused livers and in vivo excretion and distribution studies were used to discern any differences between these two strains. These strains have previously been shown to differ in their susceptibility to monocrotaline-induced pulmonary hypertension. Hepatic phase I metabolism appears to be similar in both strains with N- oxidation and dehydrogenation to the reactive pyrroles as the major pathways. During the liver perfusions, SD rats generated more monocrotalic acid than F344 rats, but the microsome and excretion studies demonstrated no significant differences in the amount of monocrotalic acid. Monocrotalic acid is a stable byproduct of dehydromonocrotaline reacting with cellular nucleophiles and indicates the amount of monocrotaline dehydrogenation when carboxylesterase activity is negligible. These data suggest that the differences in strain susceptibility to pulmonary vascular toxicity is most likely due to differences in their response to the toxic metabolites.
AB - The metabolism and distribution of 14C-monocrotaline in Fisher 344 (F344) rats was compared with that in Sprague-Dawley (SD) rats. In vitro microsomal preparations, in situ isolated perfused livers and in vivo excretion and distribution studies were used to discern any differences between these two strains. These strains have previously been shown to differ in their susceptibility to monocrotaline-induced pulmonary hypertension. Hepatic phase I metabolism appears to be similar in both strains with N- oxidation and dehydrogenation to the reactive pyrroles as the major pathways. During the liver perfusions, SD rats generated more monocrotalic acid than F344 rats, but the microsome and excretion studies demonstrated no significant differences in the amount of monocrotalic acid. Monocrotalic acid is a stable byproduct of dehydromonocrotaline reacting with cellular nucleophiles and indicates the amount of monocrotaline dehydrogenation when carboxylesterase activity is negligible. These data suggest that the differences in strain susceptibility to pulmonary vascular toxicity is most likely due to differences in their response to the toxic metabolites.
KW - Fisher 344
KW - liver perfusion
KW - metabolism
KW - monocrotalic acid
KW - monocrotaline
KW - pyrrolizidine alkaloid
KW - Sprague-Dawley
UR - http://www.scopus.com/inward/record.url?scp=0030909104&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0030909104&partnerID=8YFLogxK
U2 - 10.1016/S0305-0491(96)00323-9
DO - 10.1016/S0305-0491(96)00323-9
M3 - Article
C2 - 9180020
AN - SCOPUS:0030909104
VL - 117
SP - 115
EP - 123
JO - Comparative biochemistry and physiology. B, Comparative biochemistry
JF - Comparative biochemistry and physiology. B, Comparative biochemistry
SN - 1096-4959
IS - 1
ER -