Lipoxygenase

5-LO catalyzes the conversion of arachidonic acid to LTA4 (see Fig. 9 for a summary of the LT synthesis pathway). The 5-LO gene (ALOX5) maps to chromosome 10q11.2, spans approximately 82 kb and is composed of 14 exons and 13 introns. Mutational analysis of the ALOX5 promoter identified two polymorphisms (—1708 G/A and —1761 G/A) and a

Figure 9 The Cys leukotriene synthesis pathway. Elevation of intracellular calcium activates phospholipase A2 (PLA2) and 5 lipoxygenase (5-LO) via a 5-lipoxygenase activating protein (FLAP) to convert arachidonic acid (AA) to LTA4. LTA4 can be converted via LTA4 hydrolase (LTA4H) to LTB4, or via LTC4 synthase (LTC4S) to LTC4 and hence LTD4 and LTE4. There are multiple potential pharmacogenetic variables which can influence LTD4 synthesis and action, including known SNPs in all the key regulatory enzymes and a promoter repeat sequence in the 5-LO (ALOX5) gene. See text for further details.

Figure 9 The Cys leukotriene synthesis pathway. Elevation of intracellular calcium activates phospholipase A2 (PLA2) and 5 lipoxygenase (5-LO) via a 5-lipoxygenase activating protein (FLAP) to convert arachidonic acid (AA) to LTA4. LTA4 can be converted via LTA4 hydrolase (LTA4H) to LTB4, or via LTC4 synthase (LTC4S) to LTC4 and hence LTD4 and LTE4. There are multiple potential pharmacogenetic variables which can influence LTD4 synthesis and action, including known SNPs in all the key regulatory enzymes and a promoter repeat sequence in the 5-LO (ALOX5) gene. See text for further details.

series of insertion or deletion mutations within the GC-rich transcription factor binding region at position —147 to — 176 bp (35). Mutant alleles at this locus (n < or >5) resulted in reduced Sp1/Erg1 binding and reporter gene transcription assessed by transient promoter-CAT transfections of HeLa cells (35). Subsequently a linear relationship was identified between the number of Sp1/Egr1 motifs and transcriptional activation using a Drosophilia SL2 co-transfection system (36).

Drazen et al. (37) undertook a retrospective analysis of a study involving 221 asthmatics and examined the pharmacogenetic significance of the Sp1/Egr1 polymorphism in determining the response to the novel 5-LO inhibitor ABT-761. In this study subjects possessing only mutant ALOX5 alleles were relatively resistant to treatment (37). Mean FEVj improved by approximately 18.8 + 3.6% (n = 64) for WT homozygotes and 23.3 + 6% (n = 40) for heterozygotes, compared with —1.2 + 2.9% (n = 10) in individuals homozygous for non-wild-type alleles (37). These data provide proof of the principle that genetic variation in the pathways responsible for regulation of LT synthesis can influence the efficacy of therapeutics targeting the pathway. Subsequently, the role of the Sp1/Egr1 polymorphism in determining responses to the leukotriene receptor antagonists (LTRAs), montelukast, and zafirlukast was evaluated in a retrospective study of 52 asthmatics (38). No pharmacogenetic effect was observed for either bronchodilator response (FEVj, FEF25-75, PEFR) or bronchoprotection (AMP challenge), however, these data were based on only 40 wild-type homozygotes (5/5) and 12 heterozygotes [5/4 (11) and 5/6 (1)] individuals (38). In summary, therefore, ALOX5 promoter polymorphism may influence the efficacy of 5-LO inhibitors, but the role of the polymorphism in determining the efficacy of CLTR1 antagonists needs further study.

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