Enzymes involved in the production of leukotrienes and related molecules

Abstract

Leukotriene (LT) receptor activation (CysLT and BLT) has been postulated to be involved in the induction of inflammatory and immediate hypersensitivity responses1-3. In particular, LTs have been implicated in the pathology of human bronchial asthma4, and two CysLT 1 receptor antagonists (montelukast and zafirlukast) and one 5-lipoxygenase (5-LO) inhibitor (zileuton) have been approved for the treatment of human bronchial asthma in several countries outside Japan. In theory LT biosynthesis inhibitors might have advantages over CysLT 1 receptor antagonists as LTB 4 has been suggested to be a mediator of inflammatory conditions3. However, there is no evidence that such inhibitors have advantages in the treatment of human bronchial asthma. In particular, a BLT receptor antagonist has been shown to inhibit neutrophil accumulation following antigen challenge of asthmatic subjects with no effect on clinical parameters, arguing against a role for either BLT receptor activation or neutrophil accumulation in this disease5. With regard to other inflammatory diseases, in psoriasis there is no evidence in clinical trials that LT biosynthesis inhibitors have any clinical efficacy and this has been used to argue that 5-LO activation has no role in this disease6. Another disease in which LTB 4 has been postulated to be a mediator is inflammatory bowel disease7. However, a double blind clinical trial has been carried out in patients with ulcerative colitis using doses of the LT biosynthesis inhibitor MK-591 that produced a 100% inhibition of LT biosynthesis over a 24 h period as measured in various assays8. In this trial, MK-591 produced effects that were no different to current therapy (sulphasalazine), suggesting that LTs do not have a major role in the pathology of this disease. Whether LTs have a role in other inflammatory diseases, such as glomerulonephritis, remains to be fully explored.