Transcriptional Regulation of CYP2C19 and its Role in Altered Enzyme Activity

Chakradhara      Rao S. Uppugunduri; Youssef      Daali; Jules      Desmeules; Pierre      Dayer; Maja      Krajinovic; Marc      Ansari

Abstract

Cytochrome P450 2C19 (CYP2C19) is involved in the metabolism of several drugs that are currently in clinical use. The gene encoding CYP2C19 is polymorphic with the existence of different alleles resulting in altered enzyme activity. In addition, CYP2C19 activity is also dependent on its basal expression levels determined by the transcriptional regulation. Genetic variations located in the CYP2C19 promoter region may alter the interaction of promoter with transcription factors causing variable transcription. Genetic variants may also influence the induction, inhibition of CYP2C19 and may as well affect drug-drug interactions involving CYP2C19 substrates. The role of various transcription factors and genetic variants in the promoter region of CYP2C19 regulating its expression are discussed in this review. Furthermore, induction and inhibition of CYP2C19 by various drugs in clinically meaningful drug interactions are also discussed.

Keywords: CYP2C19, transcription, promoter, transcription factor, genetic variants, induction, inhibition, drug interaction, Transcriptional Regulation, Cytochrome P450, PPIs, hydrogen bond acceptors, intermediate metabolizers, extensive metabolizers, endogenous factors, genotype-phenotype association, GRE.