From Genotype to Phenotype: Cytochrome P450 2D6-Mediated Drug Clearance in Humans

• DOI: 10.1021/acs.molpharmaceut.6b00920
• Publication Date: 2017-02-17T16:38:32Z
• Authors: Jie Gao; Xin Tian; Jun Zhou; Ming-Zhu Cui; Hai-Feng Zhang; Na Gao; Qiang Wen; Hai-Ling Qiao
• Keywords: Genotype-phenotype distinction

How genotypic variation results in phenotypic differences is still a challenge for biology. In the field of drug metabolism, means by which specific cytochrome P4502D6 (CYP2D6) genotypes yield different phenotypes at various levels (molecular, cellular, and organismal) an important question, as CYP2D6 activity can contribute to adverse reactions. Herein, genotype was determined along with absolute content microsomal protein per gram liver human microsomes, molecular, cellular (microsomal, tissue, organ), organismal phenotype determined; effect on each CYP2D6-mediated dextromethorphan clearance (CL) delineated, overall genotype-phenotype relationship charted. We demonstrate that changes CL are markedly greater than seen molecular level. With individuals carrying 1661CC polymorphism, example, most noticeable change took place organ (4.17-fold), followed tissue (3.75-fold), organism (3.69-fold), (3.09-fold), (1.66-fold) phenotypes. addition, biggest intragenotype individual coefficient observed 1661GG individuals, reached 104.5%, 100TT, 100CT, 1661GC, 100CC, polymorphisms (102.7%, 62.4%, 53.5%, 49.7%, 44.8%, respectively). Our study has allowed us chart from level well determine genotype.