Effect of 24 cytochrome P450 2D6 variants found in the Chinese population on theN-demethylation of amitriptylinein vitro

Abstract

Context: Amitriptyline (AT), one of the tricyclic antidepressants, is still widely used for the treatment of the depression and control of anxiety states and panic disorders in the developing countries. Objective: This study evaluates the catalytic activities of CYP2D6*1, CYP2D6*2, CYP2D6*10 and 22 novel alleles in Han Chinese population and their effects on the N-demethylation of AT in vitro. Materials and methods: CYP2D6*1 and 24 CYP2D6 allelic variants were highly expressed in insect cells, and all variants were characterized using AT as a substrate. Reactions were performed at 37 C with 10-1000 lM substrate for 30 min. We established a HPLC method to quantify the levels of nortriptyline (NT). The kinetic parameters K m , V max and intrinsic clearance (V max /K m ) of NT were calculated. Results: Among the 24 CYP2D6 variants, all variants exhibited decreased intrinsic clearance values compared with wild-type CYP2D6.1. Kinetic parameters of two CYP2D6 variants (CYP2D6*92, *96) could not be determined because of absent enzyme activities. Conclusions: The comprehensive in vitro assessment of CYP2D6 variants provides significant insight into allele-specific activity towards AT in vivo.ARTICLE HISTORY

Transfer learning enables prediction ofCYP2D6haplotype function

“…We validate the genotype-based activity predictor and star allele classifier using in vitro data from literature. We identified two sets of studies to use for validation: (1) a functional characterization of 49 CYP2D6 star alleles performed using three substrates, and (2) eight in vitro studies of eleven CYP2D6 star alleles discovered in Han Chinese subjects using ten substrates [45][46][47][48][49][50][51][52][53][54] . We exclude fourteen star alleles which were found in our training data, and evaluate on measurements for 46 star alleles that were not in our training data.…”