METABOLISM AND PATHOLOGY OF MONOCROTALINE

Project: Research project

Project Details

Description

Pyrrolizidine alkaloids (PAs) are plant derived toxins that have been
shown to contaminate human and animal food sources. This contamination
is responsible for numerous toxic syndromes and PAs are known mutagens
and carcinogens. The PA monocrotaline (MCT) is of particular interest
because of its toxic effects on the lungs and heart. Rats administered
MCT or its metabolite monocrotaline pyrrole (MCTP), a known alkylating
agent, develop a pulmonary vascular syndrome that is widely used as a
model to study the pathogenesis of human pulmonary hypertension.
Pulmonary hypertension is a common pathologic sequelae of a variety of
chronic pulmonary diseases, several of which are associated with
environmental or occupational exposure to pneumotoxic chemicals. While
much is known regarding the progression of pulmonary vascular lesions
leading to hypertension and cor pulmonale, the initiating mechanisms in
pulmonary hypertension caused by MCT and other pathologic processes are
poorly characterized. current research suggests the following hypothesis
of MCT's action: Monocrotaline is activated in the liver to a
metabolite, that is sequestered in red blood cells (RBC')s where it is
stabilized during transport to the lung and causes non-cytotoxic but
irreversible endothelial injury. this injury results in deficiency in
the endothelial fluid barrier and the resultant increased fluid
transudation stimulates the arteriolar response that leads to
hypertension. We plan to characterize MCT metabolites, the nature and mechanism of RBC
sequestration of MCT metabolites, determining whether the RBC plays an
active or passive role in the transport process, documenting the nature,
progression and location of permeability changes induced in the lung by
MCT treatment and characterizing the potential pathogenetic and
toxicologic mechanisms of endothelial cell injury. We will use an
integrative approach to these questions using biosynthesized,
radiolabeled MCT and its metabolites for experiments in vivo and in
isolated organ systems, and cell culture, as well as molecular biological
techniques to determine the mechanisms of MCT metabolism, transport, and
target cell toxicity in the lung.
StatusFinished
Effective start/end date1/1/933/31/08

Funding

  • National Institutes of Health: $373,908.00
  • National Institutes of Health: $385,127.00

ASJC

  • Medicine(all)

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