Mechanisms and pathology of monocrotaline pulmonary toxicity

Dennis W Wilson, H. J. Segall, L. C. Pan, M. W. Lame, J. E. Estep, D. Morin

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Abstract

Monocrotaline (MCT) is an 11-membered macrocyclic pyrrolizidine alkaloid (PA) that causes a pulmonary vascular syndrome in rats characterized by proliferative pulmonary vasculitis, pulmonary hypertension, and cor pulmonale. Current hypotheses of the pathogenesis of MCT-induced pneumotoxicity suggest that MCT is activated to a reactive metabolite(s) in the liver and is then transported by red blood cells (RBCs) to the lung, where it initiates endothelial injury. While several lines of evidence support the requirement of hepatic metabolism for pneumotoxicity, the mechanism and relative importance of RBC transport remain undetermined. The endothelial injury does not appear to be acute cell death but rather a delayed functional alteration that leads to disease of the pulmonary arterial walls by unknown mechanisms. The selectivity of MCT for the lung, as opposed to that of other primarily hepatoxic PAs, appears likely to be a consequence of the differences in hepatic metabolism and blood kinetics of MCT. A likely candidate for a reactive metabolilte of MCT is the dehydrogenation product monocrotaline pyrrole (MCTP). Secondary or phase II metabolism of MCT through glutathione (GSH) conjugation has been characterized recently and appears to represent a detoxification pathway. The role of inflammation in the progression of MCT-induced pulmonary vascular disease is uncertain. Both perivascular inflammation and platelet activation have been proposed as processes contributing to the response of the vascular media. This review presents the experimental evidence supporting these hypotheses and outlines additional questions that arise from them.

Original languageEnglish (US)
Pages (from-to)307-325
Number of pages19
JournalCritical Reviews in Toxicology
Volume22
Issue number5-6
StatePublished - 1992

Keywords

  • Monocrotaline
  • Pulmonary hypertension
  • Pulmonary pathology
  • Pyrrolizidine alkaloids

ASJC Scopus subject areas

  • Toxicology

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    Wilson, D. W., Segall, H. J., Pan, L. C., Lame, M. W., Estep, J. E., & Morin, D. (1992). Mechanisms and pathology of monocrotaline pulmonary toxicity. Critical Reviews in Toxicology, 22(5-6), 307-325.