The endogenous substrates of brain CYP2D

Wang, Xiaoshuang; Li, Jie; Dong, Guicheng; Yue, Jiang

doi:10.1016/j.ejphar.2013.12.025

Cited by 54 publications

(40 citation statements)

References 89 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…If, as it has been suggested, the rs2032582 and rs1045642 polymorphisms affect P‐gp conformation and recycling time (Fung et al, ), the possibility arises that they indirectly affect Cav‐1 and DISC‐1 function with whatever consequences that may have with respect to antipsychotic drug response (along the lines of this argument, Cav‐1 knock‐out mice are resistant to atypical antipsychotics; Allen, Yadav, Setola, Farrell, & Roth, ]). CYP2D6, on the other hand, is also expressed in neurons, in many brain structures, where it catalyzes the formation of dopamine and serotonin from tyramine and 5‐hydroxytryptamin, respectively, and is involved in the metabolism of many neurosteroids (Anna Haduch, Bromek, & Daniel, ; Wang, Li, Dong, & Yue, ). In the past, CYP2D6 LOF alleles have been associated with personality traits in healthy volunteers (Penas, Dorado, Pacheco, Gonzalez, & LLerena, ) and CYP2D6 gene duplications with suicidality (Ingelman‐Sundberg, Persson, & Jukic, ).…”

Section: Discussionmentioning

confidence: 99%

ABCB1 and CYP2D6 polymorphisms and treatment response of psychotic patients in a naturalistic setting

Papazisis

Goulas

Sarrigiannidis

et al. 2017

Human Psychopharmacology

View full text Add to dashboard Cite

Objectives: The aim of our study was to examine the association between ABCB1 polymorphisms G2677T/A (rs2032582) and C3435T (rs1045642) and common CYP2D6 variants, with the response to antipsychotic treatment of psychotic patients, in a naturalistic setting, in Greece.Methods: One hundred patients suffering from schizophrenia and other psychotic disorders were included in the study. Dosages were normalized to chlorpromazine equivalents. Response following 1 month of treatment was assessed as either a continuous variable, using the distribution of the corrected Positive and Negative Syndrome Scale percent change, or as a dichotomous variable defined as the number of patients scoring ≥30% from the corrected baseline Positive and Negative Syndrome Scale score. Genotyping was achieved with established polymerase chain reaction-restriction fragment length polymorphism methods.Results: With response treated as a continuous variable, the homozygous recessive rs2032582 genotypes (TT) who were simultaneously carriers of a loss-of-function CYP2D6 allele (*4 or *5) responded significantly worse than the rest of the patients. Comparison of genotype frequencies revealed a statistically significant association of the above combination. No significant association between chlorpromazine equivalents and the tested genotypes was detected. Conclusion:We have detected a possible interaction between ABCB1 and CYP2D6 in affecting response of psychotic patients to drug treatment, in a naturalistic setting.

show abstract

Section: Discussionmentioning

confidence: 99%

ABCB1 and CYP2D6 polymorphisms and treatment response of psychotic patients in a naturalistic setting

Papazisis

Goulas

Sarrigiannidis

et al. 2017

Human Psychopharmacology

View full text Add to dashboard Cite

show abstract

“…The CYP2D6 enzyme is involved in the metabolism of a variety of endogenous compounds which may be affected in CYP2D6*4 carriers [40]. In addition apart from predominantly endoplasmic reticulum-targeted CYP2D6 mitochondrial targeting of CYP2D6 has also been described in the PD relevant dopaminergic neurons [41].…”

Section: Discussionmentioning

confidence: 99%

Further evidence for the association of CYP2D6*4 gene polymorphism with Parkinson’s disease: a case control study

et al. 2017

View full text Add to dashboard Cite

BackgroundGenetic and environmental risk factors play an important role for the susceptibility to sporadic Parkinson’s disease (PD). It was hypothesized that a splice variant of the CYP2D6 gene (CYP2D6*4 allele) is associated with PD because it alters the ability to metabolize toxins and in particular neurotoxins. CYP2D6 codes for the drug metabolizing enzyme debrisoquine 4-hydroxylase. The CYP2D6*4 variant results in an undetectable enzyme activity and consequently in a reduction in metabolism of some toxins.MethodsSome of agricultural chemicals have neurotoxic potential and CYP2D6 is involved in their detoxification. Thus, we conducted a case control study to investigate the association of the CYP2D6*4 with PD in a Pakistani subpopulation that is known to be exposed to high levels of some agricultural pesticides, insecticides and herbicides.ResultsWe found a significantly higher allele and genotype frequency of the CYP2D6*4 variant in 174 sporadic PD patients when compared to 200 controls. In addition, there was a trend to an earlier age of PD onset and a tremor dominant phenotype in CYP2D6*4 variant carriers.ConclusionOur data provide further evidence that a poor metabolizer status may increase the risk to develop PD especially in populations that are exposed to environmental toxins.

show abstract

“…Six homologues of CYP2D6 have been isolated in rats: CYP2D1, CYP2D2, CYP2D3, CYP2D4, CYP2D5 and CYP2D18. As CYP2D1 and CYP2D5 share a very high level of nucleotide identity (>95%) and CYP2D18 is regarded as a variant of CYP2D4 (Wang et al ., ), we determined the mRNA levels of CYP2D1/5, CYP2D2, CYP2D3 and CYP2D4/18 in various brain regions. miR‐128 is encoded by two separate genes, miR‐128‐1 and miR‐128‐2 , and miR‐128‐2 deficiency results in an 80% reduction of miR‐128 expression in the forebrain (O'Carroll and Schaefer, ).…”

Section: Methodsmentioning

confidence: 99%

“…Cytochrome P450 2D6 (CYP2D6), one of the major functional P450 isoforms present in the brain (Dutheil et al ., ; Wang et al ., ; Bromek et al ., ; Mann and Tyndale, ), is involved in the metabolism of exogenous neurotoxins, endogenous neurosteroids and neurotransmitters (Haduch et al ., ; Wang et al ., ). Brain CYP2D protein has been found in neurons as well as glia in various brain regions in rodents and humans (Dutheil et al ., ).…”

Section: Introductionmentioning

confidence: 97%

Sex hormones regulate cerebral drug metabolism via brain miRNAs: down‐regulation of brain CYP2D by androgens reduces the analgesic effects of tramadol

Xie

Wang

et al. 2015

British J Pharmacology

Self Cite

View full text Add to dashboard Cite

Background and Purpose Brain cytochrome P450 2D (CYP2D) metabolises exogenous neurotoxins, endogenous substances and neurotransmitters. Brain CYP2D can be regulated in an organ‐specific manner, but the possible regulatory mechanisms are poorly understood. We investigated the involvement of miRNAs in the selective regulation of brain CYP2D by testosterone and the corresponding alteration of the pharmacological profiles of tramadol by testosterone. Experimental Approach The regulation of CYP2D and brain‐enriched miRNAs by testosterone was investigated using SH‐SY5Y cells, U251 cells, and HepG2 cells as well as orchiectomized growth hormone receptor knockout (GHR‐KO) mice and rats. Concentration–time curves of tramadol in rat brain were determined using a microdialysis technique. The analgesic action of tramadol was assessed by the tail‐flick test in rats. Key Results miR‐101 and miR‐128‐2 bound the 3′‐untranslated region of the CYP2D6 mRNA and decreased its level. Testosterone decreased CYP2D6 catalytic function via the up‐regulation of miR‐101 and miR‐128‐2 in SH‐SY5Y and U251 cells, but not in HepG2 cells. Orchiectomy decreased the levels of miR‐101 and miR‐128‐2 in the hippocampus of male GHR‐KO mice, indicating that androgens regulate miRNAs directly, not via the alteration of growth hormone secretion patterns. Changes in the pharmacokinetic and pharmacodynamic profiles of tramadol by orchiectomy was attenuated by either testosterone supplementation or a specific brain CYP2D inhibitor. Conclusions and Implications The selective regulation of brain CYP2D via brain‐enriched miRNAs, following changes in androgen levels, such as in testosterone therapy, androgen deprivation therapy and/or ageing may alter the response to centrally active substances.

show abstract

The endogenous substrates of brain CYP2D

Cited by 54 publications

References 89 publications

ABCB1 and CYP2D6 polymorphisms and treatment response of psychotic patients in a naturalistic setting

ABCB1 and CYP2D6 polymorphisms and treatment response of psychotic patients in a naturalistic setting

Further evidence for the association of CYP2D6*4 gene polymorphism with Parkinson’s disease: a case control study

Sex hormones regulate cerebral drug metabolism via brain miRNAs: down‐regulation of brain CYP2D by androgens reduces the analgesic effects of tramadol

Contact Info

Product

Resources

About