CYP2D6 in the brain: Genotype effects on resting brain perfusion

J Kirchheiner (1) , Angela Seeringer (1) , Ana Leonor Godoy (1) , Christiane Maier (1) , Petra Beschoner (1) , Eun-Jin Sim (1) , Roberto Viviani (1) , Barbara Ohmle (1)

1 Universität Ulm - Ulm University [Ulm, Allemagne]

The cytochrome P450 2D6 (CYP2D6) is a genetically polymorphic enzyme involved in the metabolism of several psychoactive drugs. Beside its expression in the liver, CYP2D6 is highly expressed in several regions of the brain such as the hippocampus, thalamus, hypothalamus, and the cortex, but its function in the brain is not well understood. CYP2D6 may also play a physiological role due to its involvement in neurotransmitter biotransformation. In this study, CYP2D6 genotyping was performed in N=188 healthy individuals and compared to brain perfusion levels at rest, which may reflect an ongoing biological processes regulating the reactivity of the individual to emotional stimuli and the detection of signals evoking fear. Relative to N=42 matched extensive metabolizers, N=14 poor metabolizers were associated with 15% higher perfusion levels in the thalamus (p=0.03 and 0.003). Effects were also present in the whole N=188 sample divided into metabolizer groups, or finely graded into seven CYP2D6 activity levels. A weaker effect was observed in the right hippocampus (p=0.05). An exploratory analysis extended to the whole brain suggested involvement of CYP2D6 in regions associated with alertness or serotonergic function. These findings support the hypothesis of a functional role of CYP2D6 in the brain.

Mots clés: CYP2D6; cytochrome P450 enzyme; resting brain perfusion; arterial spin labeling; drug metabolism; brain biotransformation

J Kirchheiner, Angela Seeringer, Ana Leonor Godoy, Christiane Maier, Petra Beschoner, et al.. CYP2D6 in the brain: Genotype effects on resting brain perfusion. Molecular Psychiatry, 2010, ⟨10.1038/mp.2010.42⟩. ⟨hal-00523675⟩