Abstract:Cytochrome P450 (CYP) isozymes vary their expression depending on the brain area, the cell type, and the presence of drugs. Some isoforms are involved in detoxification and/or toxic activation of xenobiotics in central nervous system. However, their role in brain metabolism and neurodegeneration is still a subject of debate. We have studied the inducibility of CYP isozymes in human neuroblastoma SH-SY5Y cells, treated with β-naphtoflavone (β-NF) or ethanol (EtOH) as inducers, by qRT-PCR, Western blot (WB), and… Show more
“…The activities of some CYPs, including CYP1A and CYP3A4, were shown to be enhanced in 3D hepatocyte models ( Shoemaker and Vukasinovic 2017 ). CYP enzymes, such as CYP1A, CYP2D6 and CYP2E1, are expressed in SH-SY5Y cells ( Fernandez-Abascal et al. 2018 ; Mann and Tyndale 2010 ).…”
Background:
Inhibition of acetylcholinesterase (AChE), a biomarker of organophosphorous and carbamate exposure in environmental and occupational human health, has been commonly used to identify potential safety liabilities. So far, many environmental chemicals, including drug candidates, food additives, and industrial chemicals, have not been thoroughly evaluated for their inhibitory effects on AChE activity. AChE inhibitors can have therapeutic applications (e.g., tacrine and donepezil) or neurotoxic consequences (e.g., insecticides and nerve agents).
Objectives:
The objective of the current study was to identify environmental chemicals that inhibit AChE activity using
in vitro
and
in silico
models.
Methods:
To identify AChE inhibitors rapidly and efficiently, we have screened the Toxicology in the 21st Century (Tox21) 10K compound library in a quantitative high-throughput screening (qHTS) platform by using the homogenous cell-based AChE inhibition assay and enzyme-based AChE inhibition assays (with or without microsomes). AChE inhibitors identified from the primary screening were further tested in monolayer or spheroid formed by SH-SY5Y and neural stem cell models. The inhibition and binding modes of these identified compounds were studied with time-dependent enzyme-based AChE inhibition assay and molecular docking, respectively.
Results:
A group of known AChE inhibitors, such as donepezil, ambenonium dichloride, and tacrine hydrochloride, as well as many previously unreported AChE inhibitors, such as chelerythrine chloride and cilostazol, were identified in this study. Many of these compounds, such as pyrazophos, phosalone, and triazophos, needed metabolic activation. This study identified both reversible (e.g., donepezil and tacrine) and irreversible inhibitors (e.g., chlorpyrifos and bromophos-ethyl). Molecular docking analyses were performed to explain the relative inhibitory potency of selected compounds.
Conclusions:
Our tiered qHTS approach allowed us to generate a robust and reliable data set to evaluate large sets of environmental compounds for their AChE inhibitory activity.
https://doi.org/10.1289/EHP6993
“…The activities of some CYPs, including CYP1A and CYP3A4, were shown to be enhanced in 3D hepatocyte models ( Shoemaker and Vukasinovic 2017 ). CYP enzymes, such as CYP1A, CYP2D6 and CYP2E1, are expressed in SH-SY5Y cells ( Fernandez-Abascal et al. 2018 ; Mann and Tyndale 2010 ).…”
Background:
Inhibition of acetylcholinesterase (AChE), a biomarker of organophosphorous and carbamate exposure in environmental and occupational human health, has been commonly used to identify potential safety liabilities. So far, many environmental chemicals, including drug candidates, food additives, and industrial chemicals, have not been thoroughly evaluated for their inhibitory effects on AChE activity. AChE inhibitors can have therapeutic applications (e.g., tacrine and donepezil) or neurotoxic consequences (e.g., insecticides and nerve agents).
Objectives:
The objective of the current study was to identify environmental chemicals that inhibit AChE activity using
in vitro
and
in silico
models.
Methods:
To identify AChE inhibitors rapidly and efficiently, we have screened the Toxicology in the 21st Century (Tox21) 10K compound library in a quantitative high-throughput screening (qHTS) platform by using the homogenous cell-based AChE inhibition assay and enzyme-based AChE inhibition assays (with or without microsomes). AChE inhibitors identified from the primary screening were further tested in monolayer or spheroid formed by SH-SY5Y and neural stem cell models. The inhibition and binding modes of these identified compounds were studied with time-dependent enzyme-based AChE inhibition assay and molecular docking, respectively.
Results:
A group of known AChE inhibitors, such as donepezil, ambenonium dichloride, and tacrine hydrochloride, as well as many previously unreported AChE inhibitors, such as chelerythrine chloride and cilostazol, were identified in this study. Many of these compounds, such as pyrazophos, phosalone, and triazophos, needed metabolic activation. This study identified both reversible (e.g., donepezil and tacrine) and irreversible inhibitors (e.g., chlorpyrifos and bromophos-ethyl). Molecular docking analyses were performed to explain the relative inhibitory potency of selected compounds.
Conclusions:
Our tiered qHTS approach allowed us to generate a robust and reliable data set to evaluate large sets of environmental compounds for their AChE inhibitory activity.
https://doi.org/10.1289/EHP6993
“…2d). These apparent inconsistencies could be explained considering the complexity of the CYP450 modulation phenomenon that can occur following different pathways involving numerous nuclear receptors as well as different dose-depending or time-depending mechanisms that can lead to a post-translational process increasing protein stability as well as transcriptional induction 26,27 . Moreover, a dose-response/time-response hormesis could be also considered as a putative explanation for our results 28 .Figure 2Vitamin E in rat prostate boosts CYP gene expression and linked enzymatic activities, and impairs the redox imbalance.…”
A large number of basic researches and observational studies suggested the cancer preventive activity of vitamin E, but large-scale human intervention trials have yielded disappointing results and actually showed a higher incidence of prostate cancer although the mechanisms underlying the increased risk remain largely unknown. Here we show through in vitro and in vivo studies that vitamin E produces a marked inductive effect on carcinogen-bioactivating enzymes and a pro-oxidant status promoting both DNA damage and cell transformation frequency. First, we found that vitamin E in the human prostate epithelial RWPE-1 cell line has the remarkable ability to upregulate the expression of various phase-I activating cytochrome P450 (CYP) enzymes, including activators of polycyclic aromatic hydrocarbons (PAHs), giving rise to supraphysiological levels of reactive oxygen species. Furthermore, our rat model confirmed that vitamin E in the prostate has a powerful booster effect on CYP enzymes associated with the generation of oxidative stress, thereby favoring lipid-derived electrophile spread that covalently modifies proteins. We show that vitamin E not only causes DNA damage but also promotes cell transformation frequency induced by the PAH-prototype benzo[a]pyrene. Our findings might explain why dietary supplementation with vitamin E increases the prostate cancer risk among healthy men. Prostate cancer is the most common human malignancy and the second leading cause of cancer death among men in western nations. The high global incidence of prostate cancer, the unsatisfactory outcomes of surgery and radiotherapy and the cost of curative therapies have led to a focus on primary prevention as a major public health goal 1,2. Supported by preclinical and epidemiological evidence, antioxidants from food and supplements are widely used to protect against cancer, but clinical trials do not sustain this concept 1,3-6 and actually showed a higher incidence of prostate cancer 7,8. Conceived to break through this issue, in 2001 the National Cancer Institute (NCI) launched SELECT (Selenium and vitamin E Cancer Prevention Trial), that showed a 17% increase in prostate cancer incidence in the vitamin E arm compared to placebo 7. A growth-promoting effect of vitamin E on organoids has recently been reported 9 , but its mechanism of action remains poorly understood. Since some cytochrome P-450 (CYP) isoforms have been found overexpressed in prostate cancer 10-15 , we suspected that vitamin E could have co-carcinogenic properties such as those involving carcinogen-bioactivating CYP-enzyme changes 16,17. Results and Discussion Our study stemmed from the observation that vitamin E treatment of the human non-tumorigenic prostate epithelial RWPE-1 cell line induces the gene expression of P450 enzymes such as CYP1A1 (activating, for example, polychlorinated biphenyls, aromatic amines, PHAs and alkylnitrosamines), CYP1A4 (activating polycyclic
“…Noteworthy, CYP2D6 protein level in human brain increased with age but decreased approximately 40% in several brain regions of PD cases ( Mann et al, 2012 ). The mice with PD induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or pesticides like maneb and qaraquat, had the decreased mRNA expression of Cyp2d22 (homolog of human CYP2D6) in nigrostriatal tissues, while nicotine or resveratrol showed the neuroprotection via up-regulating Cyp2d22 expression ( Singh et al, 2009 ; Srivastava et al, 2012 ), demonstrating the neuroprotective effects of CYP2D22/CYP2D6-mediated DA synthesis or neurotoxin metabolism ( Fernandez-Abascal et al, 2018 ).…”
Section: Alterations In Expressions and Functions Of Cytochrome P450smentioning
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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