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.
Showing the most recent 10 out of 25 publications
