Pharmacogenetics of the 5-lipoxygenase pathway in asthma

It is now well appreciated that asthma is a chronic inflammatory disease of the airways; among the inflammatory cells that have been implicated in the asthmatic lesion are eosinophils and mast cells. Although these cells have the capacity to produce a number of distinct chemical mediators, the cysteinyl leukotrienes have recently been identified as important mediators of the asthmatic response. The leukotrienes are derived from arachidonic acid released from membrane phospholipids by the action of phospholipases. The archidonic acid so released in the presence of the 5-lipoxygenase (5-LO) activating protein becomes a substrate for the enzyme 5-LO. This enzyme catalyses the stereo-specific addition of molecular oxygen to arachidonic acid to form the product known as leukotriene A4. Leukotriene A4 subsequently becomes a substrate for one of two enzymes, leukotriene A4 epoxide hydrolase or LTC4 synthase. The former catalyses the formation of LTB4 while the later catalyses the formation of the cysteinyl leukotrienes. Thus the enzyme 5-LO is critically posed to serve as a regulator of leukotriene synthesis. 5-LO action is known to be regulated at a number of levels; the mechanisms include regulation of action of the mature protein and regulation of 5-LO gene transcription and translation; there is good reason to believe that all forms of 5-LO regulation are highly interdependent. In this regard we describe the presence and functional consequences of a series of naturally occurring mutations in 5-LO core promoter. These mutations modify gene transcription in vitro, and may have functional consequences in vivo.