| The relationship between the concentration of the pyrrolizidine alkaloid monocrotaline and the pattern of metabolites released from the isolated liver. | |
| | |
MedLine Citation:
|
PMID: 7839357 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
|
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. |
| | |
Authors:
|
C C Yan; R J Huxtable |
Related Documents
:
|
4004937 - The disposition of pyrimethamine in the isolated perfused rat liver. 3603677 - Levels of purine compounds in a perfusate as a biochemical marker of ischemic injury of... 6376897 - Perfusion preservation of cadaver rat pancreas: i. morphological observation and biolog... 6978837 - Suppression of lymphocyte activation by a protein released from isolated perfused rat l... 1211077 - An inhibitory effect of polyphloretin phosphate (ppp) on local anaesthesia. 3196927 - Anterior neocortical kindling in vasopressin-deficient rats. |
Publication Detail:
|
Type: In Vitro; Journal Article; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
|
Title: Toxicology and applied pharmacology Volume: 130 ISSN: 0041-008X ISO Abbreviation: Toxicol. Appl. Pharmacol. Publication Date: 1995 Jan |
Date Detail:
|
Created Date: 1995-02-24 Completed Date: 1995-02-24 Revised Date: 2007-11-14 |
Medline Journal Info:
|
Nlm Unique ID: 0416575 Medline TA: Toxicol Appl Pharmacol Country: UNITED STATES |
Other Details:
|
Languages: eng Pagination: 1-8 Citation Subset: IM |
Affiliation:
|
Department of Pharmacology, College of Medicine, University of Arizona, Tucson 85724. |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
Analysis of Variance Animals Bile / drug effects, metabolism Carcinogens / metabolism Dose-Response Relationship, Drug Glutathione / analogs & derivatives, metabolism Liver / drug effects*, metabolism Mass Spectrometry Monocrotaline / analogs & derivatives, metabolism, toxicity* Perfusion Pyrroles / metabolism* Rats |
| Grant Support | |
ID/Acronym/Agency:
|
HL-25258/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
|
0/7-glutathionyl-6,7-dihydro-1-hydroxymethyl-5H-pyrrolizine; 0/Carcinogens; 0/Pyrroles; 23291-96-5/monocrotaline pyrrole; 26400-45-3/dehydroretronecine; 315-22-0/Monocrotaline; 70-18-8/Glutathione |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: Susceptibility to insulin-dependent diabetes mellitus and short cytoplasmic ATP-binding domain TAP2*...
Next Document: Müller cell involvement in methanol-induced retinal toxicity.