Genetic polymorphisms of CYP enzymes and its influence on drug interactions between isoflavonoid genistein and model drugs

Abstract

Genetic polymorphism in cytochrome P450 (CYP) family of enzymes is a rather frequent cause of serious problems with proper dosing of drugs. This effect may be augmented by drug interaction between concomitantly taken drugs which are metabolized by the same enzymes. The second interacting partner however may easily be a compound of a natural origin as it is in the case of flavonoids from the grapefruit juice. We examined the effect of a prototypic isoflavonoid, genistein, on metabolism of probe drug substrates in genotypized human liver microsomes corresponding to slow, extensive or intermediate metabolizers with respect to CYP. The results document the most prominent effect of genistein and CYP2C19*2 allele on activity of this enzyme in slow metabolizers (down to aprox. 10%); the least effect was observed with CYP2D6*4 and CYP2D6*41 alleles (to about 60% of control value). In other words, inhibition of CYP activities by isoflavonoid (genistein) may be easily augmented by presence of defective alleles in patients of phenotypes of slow or intermediate metabolizers. Supported by a GACR P303/12/G163 Center of Excellence Project and by a Palacky University student´s project IGA_LF_2016_006.