CYP2D6 in the brain: genotype effects on resting brain perfusion

Abstract

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. The CYP2D6 enzyme may also have a physiological role due to its involvement in neurotransmitter biotransformation. In this study, CYP2D6 genotyping was performed in N = 188 healthy individuals and compared with brain perfusion levels at rest, which may reflect an ongoing biological process 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 the 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.

Genetic variability of drug-metabolizing enzymes: the dual impact on psychiatric therapy and regulation of brain function

“…Two genetic neuroimaging studies on separate samples reported an association between specific brain areas and CYP2D6 genotypes. Kirchheiner et al 108 tested the existence of such an association in rest perfusion levels in healthy participants, detecting an effect of CYP2D6 polymorphism on rest perfusion in the thalamus, hypothalamus, posterior cerebral cortex and isolated parts of the medial temporal lobe and orbitofrontal cortex, with PMs having higher perfusion levels (see Figure 4). This pattern suggested an association with brain circuits involved in vigilance.…”

Cytochrome P450–mediated drug metabolism in the brain

“…[13][14][15]19 Some of the earliest indications that brain CYPs may have important neurologic endogenous functions came from personality testing, where individuals with a CYP2D6 poor metabolizer genotype and phenotype were observed to have different personality traits than CYP2D6 normal metabolizers. 65 Several studies of this type have shown an effect of genetic variability in CYP2D6 on personality, [66][67][68] and recently this has been linked more closely to the brain in reports where different CYP2D6 genotypes were found to be associated with different resting brain perfusion rates 69 and with different levels of brain activation during a cognitive task. 70 Similar associations of genotype and personality or mood have been observed for CYP2C19, CYP2E1 and CYP19 (aromatase).…”

Effects of large-scale nonstationarity on parametric maps. A study of rest perfusion CASL data

“…These patterns are visible when statistical parametric maps are thresholded at uncorrected levels to display the estimated effects. In our work, CASL was applied to study individual differences in baseline perfusion defined by psychological variables or genotypic variants (Abler et al, 2008;Beschoner et al, 2008;Kirchheiner et al, 2010;Viviani et al, 2010a). We noted that the same patterns tended to arise in t maps of linear estimates of individual differences, even if the explanatory variables used across studies had little relation to each other, sometimes confounding the interpretation of clusters of effects.…”