Beyond eNOS: Genetic influence in NO pathway affecting drug response

Nitric Oxide (NO) has important biological functions, and its production may be influenced by genetic polymorphisms. Since NO mediates the drug response, the same genetic polymorphism that alter NO levels may also impact drug therapy. The vast majority of studies in the literature that assess the genetic influence on NO-related drug response focus on NOS3 (which encodes endothelial nitric oxide synthase), however several other proteins are interconnected in the same pathway and may also impact NO availability and drug response. The aim of this study was to review the literature regarding genetic polymorphisms that influence NO in response to pharmacological agents located in genes other than NOS3. Articles were obtained from Pubmed and consisted of 17 manuscripts that assessed polymorphisms of the following targets: Arginases 1 and 2 (ARG1 and ARG2), dimethylarginine dimethylaminohydrolases 1 and 2 (DDAH1 and DDAH2), and vascular endothelial growth factor (VEGF). Here we analyze the main results of these articles, which show promising evidences that may suggest that the NO-driven pharmacological response is affected by more than the eNOS gene. The search for genetic markers may result in better understanding of the variability of drug response and turn pharmacotherapy involving NO safer and more effective.