The lung has a unique toxicology in that metabolites of substances absorbed from the gastrointestinal tract are released from the liver and delivered to the lung, the next organ in line, in a relatively concentrated form. The pyrrolizidine alkaloids comprise a major group of liver and lung toxins exhibiting many aspects of scientific and clinical interest. Hepatic metabolites of these substances produce megalocytosis and cirrhosis of the liver, and can also damage the cardiopulmonary system, producing pulmonary arterial hypertension, right ventricular hypertrophy and cor pumonale. This pattern of toxicity is due to a complex interaction of metabolism, transport, reaction and degradation in the liver, blood, lungs and right heart. Pyrrolizidine poisoning is a major public health problem. Wide- spread outbreaks occur in underdeveloped nations as a result of food contamination and the folk medicinal use of pyrrolizidine-containing plants. In the industrialized nations, poisoning occur as a result of the use of pyrrolizidine-containing food supplements. Intoxication of life stock is a significant economic problem in the United States. This study aims to uncover the factors controlling the production and release of novel pneumotoxic liver metabolites, such as 7-glutathionyldehydroretronecine, and the further metabolites of this substance. We plan to investigate the mechanism of interaction in the lungs which results in the subsequent development of pulmonary arterial hypertension and right ventricular hypertrophy. It appears that thiol conjugates of pyrroles serve as transportable and stabilized delivery systems for alkylating pyrroles. The mechanism of transfer to lungs will be investigated, and the involvement of enzyme systems such flavin monooxygenase. The roles of alterations in potassium flux in vascular smooth muscle, of various pulmonary endothelial activities, and the interactions between these two cell types in the development of pulmonary disease will be investigated. The complex processes of pyrrolizidine alkaloid poisoning which we are uncovering yield insight into the molecular mechanism whereby pulmonary arterial hypertension, right ventricular hypertrophy, and cor pulmonary develop. In addition, the mechanism of pyrrolizidine poisoning can serve as a general paradigm for liver-lung interactions, while understanding how toxicity occurs allows rational intervention in the disease process. Experimental systems to be employed include the intact rat, isolated perfused liver, isolated perfused lung, Langendorff-perfused heart and liver microsomes.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL025258-14
Application #
3338025
Study Section
Toxicology Subcommittee 2 (TOX)
Project Start
1979-09-28
Project End
1995-03-31
Budget Start
1993-04-01
Budget End
1994-03-31
Support Year
14
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of Arizona
Department
Type
Schools of Medicine
DUNS #
City
Tucson
State
AZ
Country
United States
Zip Code
85721
Yan, C C; Huxtable, R J (1996) Effect of the pyrrolizidine alkaloid monocrotaline on taurine and sulfur amino acid metabolism in the rat liver. Adv Exp Med Biol 403:135-45
Yan, C C; Huxtable, R J (1996) The effect of the hepatotoxic pyrrolizidine alkaloid, retrorsine, on bile composition in the rat in vivo. Proc West Pharmacol Soc 39:19-22
Yan, C C; Huxtable, R J (1996) Effect of taurine on toxicity of the pyrrolizidine alkaloid monocrotaline in rats. Adv Exp Med Biol 403:315-25
Copper, R A; Bowers, R J; Beckham, C J et al. (1996) Preparative separation of pyrrolizidine alkaloids by high-speed counter-current chromatography. J Chromatogr A 732:43-50
Cooper, R A; Huxtable, R J (1996) A simple procedure for determining the aqueous half-lives of pyrrolic metabolites of pyrrolizidine alkaloids. Toxicon 34:604-7
Yan, C C; Huxtable, R J (1996) Effects of taurine and guanidinoethane sulfonate on toxicity of the pyrrolizidine alkaloid monocrotaline. Biochem Pharmacol 51:321-9
Huxtable, R J; Yan, C C; Wild, S et al. (1996) Physicochemical and metabolic basis for the differing neurotoxicity of the pyrrolizidine alkaloids, trichodesmine and monocrotaline. Neurochem Res 21:141-6
Yan, C C; Cooper, R A; Huxtable, R J (1995) The comparative metabolism of the four pyrrolizidine alkaloids, seneciphylline, retrorsine, monocrotaline, and trichodesmine in the isolated, perfused rat liver. Toxicol Appl Pharmacol 133:277-84
Yan, C C; Huxtable, R J (1995) The relationship between the concentration of the pyrrolizidine alkaloid monocrotaline and the pattern of metabolites released from the isolated liver. Toxicol Appl Pharmacol 130:1-8
Cooper, R A; de Freitas, J C; Porreca, F et al. (1995) The sea anemone purine, caissarone: adenosine receptor antagonism. Toxicon 33:1025-31

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