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.
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