Effects of genetic variability of CYP2D6 on neural substrates of sustained attention during on-task activity

Abstract

The polymorphic drug-metabolizing enzyme CYP2D6, which is responsible for the metabolism of most psychoactive compounds, is expressed not only in the liver, but also in the brain. The effects of its marked genetic polymorphism on the individual capacity to metabolize drugs are well known, but its role in metabolism of neural substrates affecting behavior personality or cognition, suggested by its CNS expression, is a long-standing unresolved issue. To verify earlier findings suggesting a potential effect on attentional processes, we collected functional imaging data while N=415 participants performed a simple task in which the reward for correct responses varied. CYP2D6 genotype was significantly associated with cortical activity in occipito-parietal areas as well as in a right lateralized network known to be activated by spatial attentional tasks. Activity in cortical areas induced by different reward levels varied less in rapid metabolizers. In conjunction with effects on reaction times, our findings provide evidence for reduced cognitive efficiency in rapid metabolizers compared to poor metabolizers in on-task attentional processes manifested through differential recruitment of a specific neural substrate. 1 

Modelling human variability in toxicokinetic and toxicodynamic processes using Bayesian meta‐analysis, physiologically‐based modelling and in vitro systems

“…The variant coding for the CYP2D6*4 allele has been found as the most frequent one leading to the PM phenotype in Caucasian populations whereas CYP2D6*10 is responsible for a decreased function in Asian populations. This allele rarely occurs in African populations and it has been hypothesised to be the likely outcome of the introgression of a Neanderthal genetic variant in Caucasians since Neanderthals have been shown to be PMs (Ingelman-Sundberg et al, 2014;Steffens et al, 2019;Viviani et al, 2020).…”

Pharmacogenomics in the era of next generation sequencing – from byte to bedside

“…One recent example of its successful use is the high-resolution confirmation of an association between HLA-C*07:01 and clozapine-induced myocarditis in patients with schizophrenia 74 . In contrast to HLA genes, CYP2D6 does not serve essential endogenous functions 75 , albeit some effects on brain physiology and function have been discussed 76,77 . However, the encoded drug A c c e p t e d M a n u s c r i p t metabolizing enzyme is responsible for the metabolism of around 20% of all clinically approved medications 78 .…”