Pyrrolizidine alkaloids (PAs) are plant derived toxins that have been shown to contaminate human and animal food sources. This contamination may be highly significant since PAs are responsible for numerous toxic syndromes and are proven mutagens and carcinogens. The PA monocrotaline is of particular interest because of its toxic effects on the lungs and heart as well as the liver. Rats administered monocrotaline (MCT) or its toxic metabolite monocrotaline pyrrole (MCTP) develop a syndrome similar to primary pulmonary hypertension in man. By injecting MCTP intravenously, pulmonary hypertension, right ventricular hypertrophy, and pulmonary vascular disease are produced. The goal of this proposal is to obtain a better understanding of the pharmacokinetics, distribution, and metabolism of the PAs that effect the heart and lung. We propose to: 1. Biosynthesize, purify, and characterize radiolabeled monocrotaline from Crotalaria retusa grown in the presence of radioactive precursors (14C and 3H). 2. Isolate and characterize significant metabolites generated from monocrotaline using both the liver and lung mixed function oxidase systems. 3. Synthesize radiolabeled and nonradiolabeled metabolites in sufficient quantities for animal experiments (rats) to determine which metabolites are important in the genesis of the pulmonary and vascular injury associated with monocrotaline administration. 4. Correlate the rate and extent of tissue distribution, covalent binding to macromolecules, and cellular location of systemically administered monocrotaline and its metabolites with morphologic evidence of cell injury in the early phase of monocrotaline induced lung and vascular injury.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Research Project (R01)
Project #
Application #
Study Section
Toxicology Study Section (TOX)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Davis
Schools of Veterinary Medicine
United States
Zip Code
Chu, P S; Lame, M W; Segall, H J (1993) In vivo metabolism of retrorsine and retrorsine-N-oxide. Arch Toxicol 67:39-43
Woods, L W; Wilson, D W; Schiedt, M J et al. (1993) Structural and biochemical changes in lungs of 3-methylindole-treated rats. Am J Pathol 142:129-38
Pan, L C; Wilson, D W; Lame, M W et al. (1993) COR pulmonale is caused by monocrotaline and dehydromonocrotaline, but not by glutathione or cysteine conjugates of dihydropyrrolizine. Toxicol Appl Pharmacol 118:87-97
Dueker, S R; Lame, M W; Segall, H J (1992) Hydrolysis of pyrrolizidine alkaloids by guinea pig hepatic carboxylesterases. Toxicol Appl Pharmacol 117:116-21
Dueker, S R; Lame, M W; Morin, D et al. (1992) Guinea pig and rat hepatic microsomal metabolism of monocrotaline. Drug Metab Dispos 20:275-80
Pan, L C; Lame, M W; Morin, D et al. (1991) Red blood cells augment transport of reactive metabolites of monocrotaline from liver to lung in isolated and tandem liver and lung preparations. Toxicol Appl Pharmacol 110:336-46
Lame, M W; Jones, A D; Morin, D et al. (1991) Metabolism of [14C]monocrotaline by isolated perfused rat liver. Drug Metab Dispos 19:516-24
Chu, P S; Segall, H J (1991) Species difference in the urinary excretion of isatinecic acid from the pyrrolizidine alkaloid retrorsine. Comp Biochem Physiol C 100:683-6
Estep, J E; Lame, M W; Morin, D et al. (1991) [14C]monocrotaline kinetics and metabolism in the rat. Drug Metab Dispos 19:135-9
Lame, M W; Morin, D; Jones, A D et al. (1990) Isolation and identification of a pyrrolic glutathione conjugate metabolite of the pyrrolizidine alkaloid monocrotaline. Toxicol Lett 51:321-9

Showing the most recent 10 out of 25 publications