Pharmacogenomics of Hypersensitivity to Non-steroidal Anti-inflammatory Drugs

Abstract

Non-steroidal anti-inflammatory drugs (NSAIDs) are extensively prescribed in daily clinical practice. NSAIDs are the main cause of drug hypersensitivity reactions all over the world. The inhibition of cyclooxygenase enzymes by NSAIDs can perpetuate arachidonic acid metabolism, shunting to the 5-lipoxygenase pathway and its downstream inflammatory process. Clinical phenotypes of NSAID hypersensitivity are diverse and can be classified into cross-reactive or selective responses. Efforts have been made to understand pathogenic mechanisms, in which, genetic and epigenetic backgrounds are implicated in various processes of NSAID-induced hypersensitivity reactions. Although there were some similarities among patients, several genetic polymorphisms are distinct in those exhibiting respiratory or cutaneous symptoms. Moreover, the expression levels, as well as the methylation status of genes related to immune responses were demonstrated to be involved in NSAID-induced hypersensitivity reactions. There is still a lack of data on delayed type reactions. Further studies with a larger sample size, which integrate different genetic pathways, can help overcome current limitations of gen etic/epigenetic studies, and provide valuable information on NSAID hypersensitivity reactions.

Keywords: asthma; epigenetic; genetic polymorphism; hypersensitivity; non-steroidal anti-inflammatory drug; urticaria.

FIGURE 1

Schematic figures of genetic and epigenetic mechanisms of NSAID hypersensitivity. Genetic effects are suggested to affect (1) arachidonic acid/cyclooxygenase pathway; (2) cytokine and intracellular activation/inactivation signaling of inflammatory cells; (3) histamine/adenosine metabolism; (4) activation of IgE receptors, and (5) HLA and MHC class II. Moreover, further studies report the involvement of (6) mutations in enzymes involved in drug metabolism and (7) epigenetic alterations. (X): NSAIDs inhibit COX enzymes; (*) indicated the pathways which are intervened by NSAIDs. APC, antigen-presenting cells; COX, cyclooxygenase; CYP, cytochrome P450; HETE, hydroxyeicosatetraenoic acid; LT, cysteinyl leukotrienes; NSAID, non-steroidal anti-inflammatory drugs; MC, mast cells; PG, prostaglandins; TX, thromboxane; UGT, UDP-UDP-glucuronosyltransferase.