The Involvement of PPARs in the Selective Regulation of Brain CYP2D by Growth Hormone

Zhang, Furong; Li, Jie; Na, Shufang; Wu, Juan; Yang, Zhongxue; Xie, Xianfei; Wan, Yu; Li, Ké; Yue, Jiang

doi:10.1016/j.neuroscience.2018.03.009

Cited by 19 publications

(14 citation statements)

References 45 publications

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“…The evidence of the induction of CYP2D6 in SH-SY5Y cells, in conflict with that observed in hepatocytes, suggests that this isoform has a different regulation in the neuroblastoma cell line. Recently, Zhang, et al [ 66 ] suggested the involvement of PPARs in the regulation of CYP2D6 in brain and SH-SY5Y cells. Conversely, the treatment with EtOH did not show a significant increase of the CYP2E1 mRNA levels, while in WB analysis we observed a statistical increase of protein levels.…”

Section: Discussionmentioning

confidence: 99%

β-Naphtoflavone and Ethanol Induce Cytochrome P450 and Protect towards MPP+ Toxicity in Human Neuroblastoma SH-SY5Y Cells

Fernandez-Abascal

Ripullone

Valeri

et al. 2018

IJMS

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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 metabolic activity assays. Immunohistochemistry was used to localize the isoforms in mitochondria and/or endoplasmic reticulum (ER). Tetrazolium (MTT) assay was performed to study the role of CYPs during methylphenyl pyridine (MPP+) exposure. EtOH increased mRNA and protein levels of CYP2D6 by 73% and 60% respectively. Both β-NF and EtOH increased CYP2E1 mRNA (4- and 1.4-fold, respectively) and protein levels (64% both). The 7-ethoxycoumarin O-deethylation and dextromethorphan O-demethylation was greater in treatment samples than in controls. Furthermore, both treatments increased by 22% and 18%, respectively, the cell viability in MPP+-treated cells. Finally, CYP2D6 localized at mitochondria and ER. These data indicate that CYP is inducible in SH-SY5Y cells and underline this in vitro system for studying the role of CYPs in neurodegeneration.

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Section: Discussionmentioning

confidence: 99%

β-Naphtoflavone and Ethanol Induce Cytochrome P450 and Protect towards MPP+ Toxicity in Human Neuroblastoma SH-SY5Y Cells

Fernandez-Abascal

Ripullone

Valeri

et al. 2018

IJMS

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“…Interestingly, brain levels of PPARc were decreased or unchanged in different areas of the brain in male GHR-/-mice, while brain PPARa expression levels in male GHR-/-mice were significantly greater than those in WT mice brain. Moreover, the results of Zhang et al (2018) demonstrated that inhibition of cerebellar CYP2D significantly affected spatial learning and exploratory behavior in mice.…”

Section: Regulationmentioning

confidence: 99%

“…A luciferase assay in the SH-SY5Y human neuroblastoma cell line revealed that the PPARc receptor activated the CYP2D6 gene promoter, while PPARa suppressed its expression (Zhang et al 2018). Furthermore, growth hormone (GH) reduced PPARa mRNA levels and enhanced mRNA levels of CYP2D6 and PPARc in SH-SY5Y cells.…”

Section: Regulationmentioning

confidence: 99%

Cytochrome P450 expression and regulation in the brain

Kuban

Daniel

2020

Drug Metabolism Reviews

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The regulation of brain cytochrome P450 enzymes (CYPs) is different compared with respective hepatic enzymes. This may result from anatomical bases and physiological functions of the two organs. The brain is composed of a variety of functional structures built of different interconnected cell types endowed with specific receptors that receive various neuronal signals from other brain regions. Those signals activate transcription factors or alter functioning of enzyme proteins. Moreover, the blood-brain barrier (BBB) does not allow free penetration of all substances from the periphery into the brain. Differences in neurotransmitter signaling, availability to endogenous and exogenous active substances, and levels of transcription factors between neuronal and hepatic cells lead to differentiated expression and susceptibility to the regulation of CYP genes in the brain and liver. Herein, we briefly describe the CYP enzymes of CYP1-3 families, their distribution in the brain, and discuss brain-specific regulation of CYP genes. In parallel, a comparison to liver CYP regulation is presented. CYP enzymes play an essential role in maintaining the levels of bioactive molecules within normal ranges. These enzymes modulate the metabolism of endogenous neurochemicals, such as neurosteroids, dopamine, serotonin, melatonin, anandamide, and exogenous substances, including psychotropics, drugs of abuse, neurotoxins, and carcinogens. The role of these enzymes is not restricted to xenobiotic-induced neurotoxicity, but they are also involved in brain physiology. Therefore, it is crucial to recognize the function and regulation of CYP enzymes in the brain to build a foundation for future medicine and neuroprotection and for personalized treatment of brain diseases.

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“…5-HT is mainly involved in some basic behavior and emotion regulation, and lack of 5-HT may lead to depressive disorder. Mouse experiments showed the decreased activity of cerebellar CYP2D by quinine resulted in a behavioral deficit related to spatial learning and memory, as well as increased anxiety-related behavior (Zhang et al, 2018), further demonstrating roles of brain CYP2Dmediated 5-HT formation. Melatonin was also detected (via its deacetylation to 5-MT) to support 5-HT synthesis via CYP2D in brain (Haduch et al, 2016).…”

Section: Serotoninmentioning

confidence: 91%

“…More importantly, the characteristics of brain CYPs and UGTs are often different from liver. For example, growth hormone receptor knockout significantly lowered brain Cyp2d mRNA levels without affecting expressions of hepatic Cyp2d in mice (Zhang et al, 2018). 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).…”

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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The Involvement of PPARs in the Selective Regulation of Brain CYP2D by Growth Hormone

Cited by 19 publications

References 45 publications

β-Naphtoflavone and Ethanol Induce Cytochrome P450 and Protect towards MPP+ Toxicity in Human Neuroblastoma SH-SY5Y Cells

β-Naphtoflavone and Ethanol Induce Cytochrome P450 and Protect towards MPP+ Toxicity in Human Neuroblastoma SH-SY5Y Cells

Cytochrome P450 expression and regulation in the brain

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

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