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CYP2C9  metabolizes approximately 20% of clinically used drugs, including the narrow therapeutic window drugs warfarin and phenytoin. More than 16,000 variants have been reported in the National Center for Biotechnology Information  CYP2C9  database, as well as 58 alleles in the official P450 Nomenclature Committee website. Two single nucleotide polymorphisms represented by the  CYP2C9*2  and  CYP2C9*3  alleles have been studied extensively. However, in addition to these two alleles, other genetic factors and an individual’s biological characteristics contribute to the overall drug phenotype. A major bottleneck for  CYP2C9  pharmacogenomics in clinical field applications is the lack of knowledge regarding the numerous genetic polymorphisms and their molecular functionalities. An unmet gap exists between the ever-growing number of genetic variants and their molecular mechanisms. In the present review, functional changes of all known  CYP2C9  protein coding alleles were predicted using  in silico  analyses and compared with the  in vitro  and  in vivo  data. We also summarize functional information from recently reported  CYP2C9  variants. Regarding the previously known  CYP2C9  variants, we provide an update on the functional information obtained from  in vitro  and  in vitro  data.

Molecular functionality of CYP2C9 polymorphisms and their influence on drug therapy