Sulfur Conjugates as Putative Pneumotoxic Metabolites of the Pyrrolizidine Alkaloid, Monocrotaline
Well over 200 pyrrolizidine alkaloids are known, distributed in a number of plant families (Huxtable, 1989; Mattocks, 1986). Important pyrrolizidine-containing families include Crotalaria, Symphytum, Heliotropium and Senecio. Alkaloids containing a 1,2-double bond (Fig. 1) are hepatotoxic, producing veno-occlusive disease in experimental animals, livestock and humans. A relatively small number of alkaloids are also pneumotoxic, producing pulmonary arterial hypertension, arterial medial hyperplasia, endothelial proliferation, and right ventricular hypertrophy in selected species (Huxtable, 1990). Pneumotoxic alkaloids include the Crotalaria lkaloids, monocrotaline and fulvine, and the Senecio alkaloids, senecionine and seneciphylline. Pulmonary hyperplasia and right ventricular hypertrophy are produced in rats by monocrotaline following a single injection of 0.12–0.36 mmole/kg, or a total dose of 0.04 mmole/kg given subacutely (Shubat, Hubbard and Huxtable, 1989). However, pneumotoxicity is delayed in appearance. Following a single injection, pulmonary hyperplasia is first detectable after seven days, pulmonary arterial blood pressure is raised after nine days, and right ventricular hypertrophy develops after fourteen days. These effects are caused by hepatic metabolites of monocrotaline. Monocrotaline itself has no effect on the isolated, perfused lung, and lung tissue appears to be incapable of metabolizing the alkaloid (Gillis, Huxtable and Roth, 1978).
KeywordsPulmonary Arterial Hypertension Ventricular Hypertrophy Serotonin Transport Perfuse Lung Pyrrolizidine Alkaloid
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