The cysteinyl leukotrienes are generated in mast cells,
basophils, macrophages, and eosinophils. These mediators
have long been suspected of being key participants
in the pathophysiology of asthma. In particular, the
powerful bronchoconstrictor activity of these leukotrienes
has implicated them as major contributors to the
reversible component of airway obstruction. Additional
evidence suggests that their pathophysiologic role extends
beyond their ability to elicit bronchoconstriction.
Thus, it is now believed that these substances stimulate
mucus secretion and microvascular leakage, both of
which contribute to airway obstruction.The relative importance
of the various actions of the cysteinyl
leukotrienes in the complex pathophysiology of asthma
is not clear.
The biological actions of the cysteinyl leukotrienes
are mediated via stimulation of CysLT1 receptors.
Montelukast and zafirlukast are competitive antagonists
of these receptors. In contrast, zileuton suppresses synthesis
of the leukotrienes by inhibiting 5-lipoxygenase, a
key enzyme in the bioconversion of arachidonic acid to
the leukotrienes. Zileuton also blocks the production of
leukotriene B4, another arachidonic acid metabolite
with proinflammatory activity.The CysLT1-receptor antagonists
alter neither the production nor the actions of
leukotriene B4.
