Hypothesis

  1. * Paroxitine strongly inhibits CYP2D6 https://pubmed.ncbi.nlm.nih.gov/9817620/
  2. * CYP2D6 Is Functional in Human Brain In Vivo https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7383223/
  3. * astroglial cells are implicated in ASD https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8583956/#:~:text=There%20are%20some%20clinical%20reports,of%20these%20cells%20%5B5%5D.
  4. * CYP2D6 is expressed in glial cells https://www.tandfonline.com/doi/full/10.1080/03602532.2020.1858856
  5. * Paroxitine passes from mother to fetus https://pubmed.ncbi.nlm.nih.gov/30105921/
  6. * Our result that Paroxitine has a strong protective effect.

Paroxetine

MBI

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7557591/

Various types of CYP450 inhibition (competitive, non-competitive, mechanism-based) have been observed clinically, and interactions of these types require a distinct clinical management strategy. This review focuses on mechanism-based inhibition, which occurs when a substrate forms a reactive intermediate, creating a stable enzyme–intermediate complex that irreversibly reduces enzyme activity. This type of inhibition can cause interactions with drugs such as omeprazole, paroxetine, macrolide antibiotics, or mirabegron.

SSRI impact

CYP2D6

Role of CYP2D6 in fetal development

CYP2D6 has been found in neurons in numerous human brain areas, including the thalamus, hypothalamus, hippocampus, substantia nigra, cerebellum, and in several layers of the frontal neocortex [4,5] raising questions about its potential role in these neurons. The enzyme was implicated in metabolism of the endogenous compounds 5-methoxytryptamine, anandamide, progesterone and tyramine and in generation of serotonin and dopamine from trace amines [6].

This hypothesis is strengthened by the fact that in a transgenic mouse model, with CYP2D6 expressed in the brain, higher serotonin levels have been measured in several brain regions, including the cerebellum and hippocampus [7]. CYP2D6 might also affect the endocannabinoid system within the CNS due to its ability to metabolize anandamide and its derivatives [8]; however, the physiological significance of such metabolism is still unclear.

Associations between CYP2D6 genotypes and personality traits gave the first indications that CYP2D6 might have endogenous functions apart from its important role in drug metabolism. In one of the first reports, it was shown that PMs displayed higher impulsivity-related traits [9], which was confirmed by a later study [10]. Others have found PMs to be more anxiety-prone and less successful in socialization when compared with EMs [11,12]. These heterogeneous results might be related to different ethnicities of the subjects and different methods used for monitoring the personality, but do suggest that CYP2D6 might have an endogenous role in the human brain influencing behavior.

The UM CYP2D6 phenotype has been suggested to predict suicidal risk [13,14] and increased suicidal behavior among individuals with eating disorders [15]. In search for a physiological effect of higher CYP2D6 brain expression in such individuals, Stingl and collaborators examined the perfusion rates in the thalamus and the right hippocampus among healthy human subjects. They detected an effect of CYP2D6 polymorphism on resting-state perfusion in the thalamus, hypothalamus, posterior cerebral cortex, and isolated parts of the medial temporal lobe and orbitofrontal cortex, where PMs had lower perfusion rates, a pattern that suggested an association with brain circuits involved in vigilance. Also, they tested the effect of the CYP2D6 polymorphism on a standard working-memory task and recognition of facial expressions, a task eliciting neural circuits related with the detection of emotionally arousing stimuli measured with fMRI. In both studies they found an effect of the CYP2D6 polymorphism in visual areas in the posterior cerebral cortex, whereas no effect could be detected in areas outside of those staked out by the previous perfusion study (see [16] and references therein). This provides an interesting mechanistic link to the findings concerning a relationship to suicide.

Effect of Cytochrome P450 2D6 Genotype on Maternal Paroxetine Plasma Concentrations during Pregnancy

Differences in CYP2D6 genotype may have divergent effects on maternal plasma paroxetine concentrations during pregnancy, with therapeutic consequences. Accumulation of paroxetine in a considerable group of pregnant women will lead to unintended increased exposure of paroxetine to the unborn child. Knowledge about a patient’s CYP2D6 genotype is indispensable when prescribing paroxetine in pregnancy

Demographic differences

  • Unique CYP2D6 activity distribution and genotype-phenotype discordance in black Americans https://pubmed.ncbi.nlm.nih.gov/12152006/ Significantly lower CYP2D6 activity in the black American group (0.016) than in a white control population (0.0044; P =.0001)

  • CYP2D6 allele frequency in European Caucasians, Asians, Africans and their descendants https://pubmed.ncbi.nlm.nih.gov/11972444/ European Caucasians and their descendants, the functional group of alleles are predominant, with a frequency of 71%. Non-functional alleles represent 26% of the variability, mainly CYP2D64. In Asians and their close descendants, functional alleles represent only ~ 50% of the frequency of CYP2D6 alleles. Asians and Pacific Islanders have a high frequency (median = 41%) of a reduced function allele, CYP2D610, contributing to the population shift to the right of metabolic rates indicating slower metabolism.

The above observations would indicate if our hypothesis is correct that ASD prevalence will be lower in africans, african americans and asians compared to caucasians, which is correct

asd genes

https://www.frontiersin.org/articles/10.3389/fnins.2022.862315/full

CYP1A2, ABCB1, ABCG2, GSTM1, and CYP2D6 and benzo-(a)-pyrene, valproic acid, bisphenol A, particulate matter, methylmercury, and perfluorinated compounds. Individuals carrying predicted damaging variants in high evidence XenoReg genes are likely to have less efficient detoxification systems or impaired physiological barriers. They can therefore be particularly susceptible to early life exposure to ubiquitous xenobiotics, which elicit neuropathological mechanisms in the immature brain, such as epigenetic changes, oxidative stress, neuroinflammation, hypoxic damage, and endocrine disruption.

need to downlaod this dataset, and find if non-functional variants of CYP2D6 are over-represented in the control population

For CNV identification we analyzed genetic data from the Autism Genome Project (AGP) consortium (N = 2,446) (accession code: phs000267.v5.p2) (Pinto et al., 2010, 2014; Supplementary Table 1) and from the Simons Simplex Collection (SSC) (N = 1,124) (Sanders et al., 2011) datasets, amounting to a total of 3,570 subjects with genome-wide CNV data. The AGP is a large-scale, international research consortium designed to identify autism candidate genes (Hu-Lince et al., 2005), while the SSC is a resource from the Simons Foundation for Autism Research (SFARI) (Fischbach and Lord, 2010) (RRID: SCR_004261). CNV data from two cohorts of subjects without clinical history of neuropsychiatric disease (NPD) (N = 9,649) was used to estimate CNV frequencies in the general population (Shaikh et al., 2009; Cooper et al., 2011; Supplementary Table 1). CNV data from these control datasets are publicly available through the Database of Genomic Variants (DGV) (MacDonald et al., 2014; RRID: SCR_007000; Supplementary Table 1). All these populations were genotyped using Illumina arrays.

ASC, AGP, and SSC datasets obtained genetic data from family trios. Maternal genetic data was available for 1,702 (63.6%) subjects from ASC, 2,241 (91.6%) subjects from AGP, and 778 (70.1%) subjects from SSC. In these subjects we assessed the transmission pattern of selected SNVs and CNVs in XenoReg genes encoding detoxification enzymes. Because some subjects may be common between these datasets, we analyzed each dataset separately.

Pharmacogenomics of CYP2D6

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692531/

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