Brain CYP2B induction can decrease nicotine levels in the brain

Garcia, Kristine L.P.; Lê, A. D.; Tyndale, Rachel F.

doi:10.1111/adb.12411

Cited by 8 publications

(4 citation statements)

References 33 publications

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“…Although we do not find inflammatory genes in this ketamine network, the drug has shown promise as an investigational therapy for some inflammatory disorders (8). We did find evidence supporting the inclusion of the pharmacokinetic genes CYP2B6 and CYP3A4, in addition to ESR1 and GRIA1, GRIA4 within the ketamine network in human brain consistent with recent studies (12,78), although more study is needed to show how proteins encoded by these genes in the brain contribute to ketamine response in humans.…”

Section: The Ketamine Pharmacogenomic Sub-networksupporting

confidence: 89%

Ketamine’s pharmacogenomic network in human brain contains sub-networks associated with glutamate neurotransmission and with neuroplasticity

Higgins

Handelman

Allyn-Feurer

et al. 2020

Preprint

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The pharmacogenomic network responsible for the rapid antidepressant action of ketamine and concomitant adverse events in patients has been poorly defined. Integrative, multiscale biological data analytics helps explain ketamine's action. Using a validated computational pipeline, candidate ketamine-response genes and regulatory RNAs from published literature, binding affinity studies, and single nucleotide polymorphisms (SNPs) from genomewide association studies (GWAS), we identified 108 SNPs associated with 110 genes and regulatory RNAs. All of these SNPs are classified as enhancers, and additional chromatin interaction mapping in human neural cell lines and tissue shows enhancer-promoter interactions involving other network members. Pathway analysis and gene set optimization identified three composite sub-networks within the broader ketamine pharmacogenomic network. Expression patterns of ketamine network genes within the postmortem human brain are concordant with ketamine neurocircuitry based on the results of 24 published functional neuroimaging studies. The ketamine pharmacogenomic network is enriched in forebrain regions known to be rapidly activated by ketamine, including cingulate cortex and frontal cortex, and is significantly regulated by ketamine (p=6.26E-33; Fisher's exact test). The ketamine pharmacogenomic network can be partitioned into distinct enhancer sub-networks associated with: (1) glutamate neurotransmission, chromatin remodeling, smoking behavior, schizophrenia, pain, nausea, vomiting, and post-operative delirium; (2) neuroplasticity, depression, and alcohol consumption; and (3) pharmacokinetics. The component sub-networks explain the diverse action mechanisms of ketamine and its analogs.These results may be useful for optimizing pharmacotherapy in patients diagnosed with depression, pain or related stress disorders. GRIA4 (12), and many other known (8,13) and unknown pharmacodynamic targets within human brain. Ketamine and its metabolites strongly induce the expression of the CYP2B6 gene in human brain, which encodes a drug metabolizing enzyme that contributes to first-and second-pass metabolism of the drug and its metabolites (14). Recent genomewide association studies (GWAS) in humans demonstrate association of ketamine response and adverse events with enhancers of genes and long non-coding RNAs (lncRNAs) related to the roundabout guidance receptor 2 (ROBO2) gene, whose product binds members of the slit guidance ligand family (SLIT1, SLIT2) that are involved in dendrite guidance and synaptic plasticity (15,16). Like phencyclidine, a structurally related compound, ketamine induces acute dissociation, with both drugs exhibiting species-specific differences in response. In sum, the central nervous system (CNS) pathway(s) responsible for the rapid antidepressant effects of ketamine and its enantiomers in patients diagnosed with treatment-resistant depression (TRD) remain poorly defined, including emergence of on-and off-target effects and individual differences in response and adverse eve...

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Section: The Ketamine Pharmacogenomic Sub-networksupporting

confidence: 89%

Ketamine’s pharmacogenomic network in human brain contains sub-networks associated with glutamate neurotransmission and with neuroplasticity

Higgins

Handelman

Allyn-Feurer

et al. 2020

Preprint

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“…CYP2B1, which corresponds to human CYP2B6, plays a major role in the metabolism of Nic in rat (Hammond et al, 1991;Al Koudsi and Tyndale, 2010). Previous studies using rats confirmed that alternating brain CYP2B activity influenced brain Nic levels and Nic-mediated behaviors (Garcia et al, 2015;Garcia et al, 2017). To investigate the effect of CYP2B inhibition on Nic biotransformation and neurotransmitter release in rat brains, another group of rats was pretreated with proadifen (50 mg kg -1 •d -1 , i. p., 4 days) in our research.…”

Section: Effect Of Proadifen Pretreatment On the Metabolism Of Nic In...mentioning

confidence: 99%

Pharmacokinetic and pharmacodynamic studies of nicotine in rat brain: a simultaneous investigation of nicotine metabolites and the release of neurotransmitters in vivo

Guo,

Mao,

Zhang

et al. 2023

Front. Chem.

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Introduction: The body’s ability to metabolize nicotine and the disposition of nicotine in the brain are important determinants of its exposure. Limited knowledge about the near real-time changes of neurochemicals during the brain nicotine metabolic process hinders the recognition of its multiple neuropharmacological effects.Methods: An online microdialysis coupled with UHPLC-HRMS/MS method for the in vivo multi-analysis of nicotine metabolites and several neurotransmitters in rat brain was developed. Whether the systemic modulation of metabolic enzyme CYP2B would modulate nicotine pharmacokinetics and local neurochemical effects was further investigated.Results: The dynamic profiles of over 10 nicotine metabolites and neurotransmitters were simultaneously obtained after a single injection of nicotine (2 mg·kg−1, i.p.) using the new method. Proadifen pretreatment (50 mg·kg−1·d−1, i.p., 4 days) caused significant inhibition of brain CYP2B1 activity. When exposed to nicotine, the brain Cmax of nicotine was 1.26 times higher and the levels of nicotine metabolites, nornicotine, and nicotine-N-oxide, were decreased by 85.3% and 34.4% in proadifen-pretreated rats. The higher level of brain nicotine induced a greater release of dopamine, serotonin, glutamate, and γ-amino-butyric acid in the nucleus accumbens. The concentrations of nicotine and dopamine were positively correlated, and the average levels of γ-amino-butyric acid and serotonin were 2.7 and 1.2 times higher, respectively, under the inhibition of nicotine metabolism.Discussion: These results demonstrated that inhibiting nicotine metabolism in rats can enhance the residence of brain nicotine and its local neurotransmitter effects. The metabolic activity of nicotine under different physiological conditions could regulate nicotine’s bioavailability and its resulting pharmacology.

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“…Human CYP2B6 and rat homolog CYP2B1 share 75% of amino acid properties, have overlapping substrate specificities, and metabolize a variety of substrates, including nicotine ( Bloom et al, 2019 ), drugs of abuse, neurotoxins, anticancer drugs, anesthetics and 5-HT. CYP2B is expressed differently in various regions of rat brain and could be induced by nicotine, but not in liver, which lowered brain nicotine levels independent of liver, increasing withdrawal symptoms ( Garcia et al, 2015 , 2017 ). Ethanol could induce CYP2B1/2 mRNA, protein and activity in rat liver rather than brain ( Schoedel et al, 2001 ) while in the caudate, putamen and cerebellum of African green monkeys, CYP2B6 protein was induced by ethanol ( Ferguson et al, 2013 ), which also affected nicotine oxidation in the body.…”

Section: Alterations In Expressions and Functions Of Cytochrome P450s And Udp-glucuronosyltransferases Under Diseases And Their Impacts Omentioning

confidence: 99%

“…The CYP2D activity and protein levels increased in the hippocampus, hypothalamus and striatum of rats with aging, but decreased in the frontal cortex and liver of senescent rats ( Haduch et al, 2020b ). Nicotine induced CYP2B mRNA and protein levels in rat brain but not in liver ( Garcia et al, 2017 ). As well, UGT1A3 mRNA was up-regulated by nicotine in humanized UGT1 mouse brain but not in liver ( Sakamoto et al, 2015 ).…”

Section: Introductionmentioning

confidence: 99%

Alterations of Cytochrome P450s and UDP-Glucuronosyltransferases in Brain Under Diseases and Their Clinical Significances

Yun

Yang

et al. 2021

Front. Pharmacol.

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Cytochrome P450s (CYPs) and UDP-glucuronosyltransferases (UGTs) are both greatly important metabolic enzymes in various tissues, including brain. Although expressions of brain CYPs and UGTs and their contributions to drug disposition are much less than liver, both CYPs and UGTs also mediate metabolism of endogenous substances including dopamine and serotonin as well as some drugs such as morphine in brain, demonstrating their important roles in maintenance of brain homeostasis or pharmacological activity of drugs. Some diseases such as epilepsy, Parkinson’s disease and Alzheimer’s disease are often associated with the alterations of CYPs and UGTs in brain, which may be involved in processes of these diseases via disturbing metabolism of endogenous substances or resisting drugs. This article reviewed the alterations of CYPs and UGTs in brain, the effects on endogenous substances and drugs and their clinical significances. Understanding the roles of CYPs and UGTs in brain provides some new strategies for the treatment of central nervous system diseases.

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Brain CYP2B induction can decrease nicotine levels in the brain

Cited by 8 publications

References 33 publications

Ketamine’s pharmacogenomic network in human brain contains sub-networks associated with glutamate neurotransmission and with neuroplasticity

Ketamine’s pharmacogenomic network in human brain contains sub-networks associated with glutamate neurotransmission and with neuroplasticity

Pharmacokinetic and pharmacodynamic studies of nicotine in rat brain: a simultaneous investigation of nicotine metabolites and the release of neurotransmitters in vivo

Alterations of Cytochrome P450s and UDP-Glucuronosyltransferases in Brain Under Diseases and Their Clinical Significances

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