LTC4 Synthase

LTC4 synthase conjugates glutathione with LTA4 to form LTC4, the first cysteinyl-leukotriene in the 5-LO pathway (Fig. 9). The human LTC4 synthase gene (LTC4S) consists of five exons, ranging between 71 bp and 257 bp, spans 2.51 kb and has been mapped to chromosome 5q35. LTC4S is a candidate gene for aspirin-intolerant asthma (AIA), a subphenotype of the disease in which patients experience cys-LT-dependent adverse respiratory reactions to aspirin and other cyclooxygenase (COX) inhibitors. A fivefold overexpression of LTC4 synthase in bronchial biopsies of AIA patients compared with aspirin-tolerant asthma (ATA) patients was demonstrated in one study; in contrast, no significant differences were observed in other enzymes involved in the biosynthesis of Cys-LTs (39). Subsequently, a — 444A/C promoter polymorphism was identified and the C variant allele was found to be more common in the AIA patients, compared with the ATA or the normal subjects (odds ratio 3.9) (40).

A small clinical study examined the role of the — 444 polymorphism in severe asthmatics compared with wild-type (AA) controls. In this study, the presence of the C allele resulted in an approximate threefold increase in LTC4 production in isolated blood eosinophils stimulated with calcium ionophore A23187 in the presence of indomethacin. The response to 2-weeks treatment with zafirlukast (20 mg bd) in severe asthmatics was influenced by the — 444 A/C polymorphism, with FEV1 increasing by 9 + 12% in individuals with the C allele and decreasing by -12+ 18% in the AA genotype group (41). Although based on small numbers, this suggests a possible pharmacoge-netic effect due to this polymorphism at the LTC4S locus.

These data support this hypothesis that the C allele is associated with increased LTC4S levels, increased LT production, and therefore greater benefit following LTRA therapy. Subsequently, these data have been supported by a study of another LTRA, pranlukast (225 mg twice daily, four weeks) in a Japanese cohort of asthmatic subjects (n = 50) (42). Carriers of the C allele (n = 17) responded better to pranlukast compared with the individuals homozygous for the A allele (n = 31) (14.3 + 5.3% vs. 3.1 + 2.4% improvement in FEV1) (42). Similarly, in a study of ATA (43) and AIA (26) patients, the greatest improvements in asthma-related outcomes (morning and evening PEFR, daytime symptom scores) following montelukast treatment (10-mg tablet per day, three weeks) was observed in carriers of the — 444C allele (43). These studies provide reasonable evidence that the LTC4S — 444A/C promoter polymorphism, which has a frequency of around 0.3 in Caucasians (44), can influence patient responses to a range of LTRAs. The molecular mechanism of this effect remains unclear, however, with conflicting data regarding the functional effects of the — 444A/C polymorphism on gene transcription (45) and the finding that other, potentially important promoter polymorphisms are present in the LTC4S gene (44). More recently, in a meta-analysis of eight studies examining the efficacy of LTRA to attenuate bronchial hyperresponsiveness, no correlation was observed between the LTC4S —444 polymorphism and clinical outcome (46).

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