A role for CYP in the drug–hormone crosstalk of the brain

Meyer, Ralf Peter; Gehlhaus, Marcel

doi:10.1517/17425251003680791

Cited by 7 publications

(10 citation statements)

References 110 publications

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“…It metabolizes therapeutically important drugs as well as drugs of abuse [31], [32]. The expression of CYP2E1 has also been reported in cultured rat [13], [33] and human brain cells [34]. The mechanism of CYP2E1 induction is complex and depends on the substrate, species, tissue, or cell type [35], [36] and in the brain regions and cell type specific expression [37].…”

Section: Introductionmentioning

confidence: 99%

Monocrotophos Induces the Expression and Activity of Xenobiotic Metabolizing Enzymes in Pre-Sensitized Cultured Human Brain Cells

et al. 2014

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The expression and metabolic profile of cytochrome P450s (CYPs) is largely missing in human brain due to non-availability of brain tissue. We attempted to address the issue by using human brain neuronal (SH-SY5Y) and glial (U373-MG) cells. The expression and activity of CYP1A1, 2B6 and 2E1 were carried out in the cells exposed to CYP inducers viz., 3-methylcholanthrene (3-MC), cyclophosphamide (CPA), ethanol and known neurotoxicant- monocrotophos (MCP), a widely used organophosphorous pesticide. Both the cells show significant induction in the expression and CYP-specific activity against classical inducers and MCP. The induction level of CYPs was comparatively lower in MCP exposed cells than cells exposed to classical inducers. Pre-exposure (12 h) of cells to classical inducers significantly added the MCP induced CYPs expression and activity. The findings were concurrent with protein ligand docking studies, which show a significant modulatory capacity of MCP by strong interaction with CYP regulators-CAR, PXR and AHR. Similarly, the known CYP inducers- 3-MC, CPA and ethanol have also shown significantly high docking scores with all the three studied CYP regulators. The expression of CYPs in neuronal and glial cells has suggested their possible association with the endogenous physiology of the brain. The findings also suggest the xenobiotic metabolizing capabilities of these cells against MCP, if received a pre-sensitization to trigger the xenobiotic metabolizing machinery. MCP induced CYP-specific activity in neuronal cells could help in explaining its effect on neurotransmission, as these CYPs are known to involve in the synthesis/transport of the neurotransmitters. The induction of CYPs in glial cells is also of significance as these cells are thought to be involved in protecting the neurons from environmental insults and safeguard them from toxicity. The data provide better understanding of the metabolizing capability of the human brain cells against xenobiotics.

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Section: Introductionmentioning

confidence: 99%

Monocrotophos Induces the Expression and Activity of Xenobiotic Metabolizing Enzymes in Pre-Sensitized Cultured Human Brain Cells

et al. 2014

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“…CYP3A metabolism of both endogenous and exogenous compounds was inhibited by alcohol in human liver (Patki et al, 2004). Induction of CYP3A4 in the frontal cortex may represent a homeostatic response to alcohol inhibition of CYP3A activity, as alterations in CYP3A activity have been proposed to affect steroid-mediated signaling in the brain (Meyer and Gehlhaus, 2010). Changes in the dopaminergic system have also been linked to altered hepatic CYP3A expression in animals (Wójcikowski et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Differential Expression of Human Cytochrome P450 Enzymes from the CYP3A Subfamily in the Brains of Alcoholic Subjects and Drug-Free Controls

et al. 2013

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Cytochrome P450 enzymes are responsible for the metabolism of most commonly used drugs. Among these enzymes, CYP3A forms mediate the clearance of around 40-50% of drugs and may also play roles in the biotransformation of endogenous compounds. CYP3A forms are expressed both in the liver and extrahepatically. However, little is known about the expression of CYP3A proteins in specific regions of the human brain. In this study, form-selective antibodies raised to CYP3A4 and CYP3A5 were used to characterize the expression of these forms in the human brain. Both CYP3A4 and CYP3A5 immunoreactivity were found to varying extents in the microsomal fractions of cortex, hippocampus, basal ganglia, amygdala, and cerebellum. However, only CYP3A4 expression was observed in the mitochondrial fractions of these brain regions. Nterminal sequencing confirmed the principal antigen detected by the anti-CYP3A4 antibody in cortical microsomes to be CYP3A4. Immunohistochemical analysis revealed that CYP3A4 and CYP3A5 expression was primarily localized in the soma and axonal hillock of neurons and varied according to cell type and cell layer within brain regions. Finally, analysis of the frontal cortex of chronic alcohol abusers revealed elevated expression of CYP3A4 in microsomal but not mitochondrial fractions; CYP3A5 expression was unchanged. The site-specific expression of CYP3A4 and CYP3A5 in the human brain may have implications for the role of these enzymes in both normal brain physiology and the response to drugs.

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“…A variety of drug-metabolizing CYPs, including CYP2B, CYP2D, CYP2E1, CYP3A, and CYP4, have been detected in the brain (Meyer and Gehlhaus, 2010;Strobel et al, 2001) and their substrates include a wide range of centrally active drugs including opiate, antipsychotic, and antidepressant medications; thus, the impact of brain CYPs may be an important determinant of drug response. Local CYPmediated metabolism of these CNS acting drugs could have a direct impact on drug efficacy and could also contribute to drug tolerance, as seen from the shifts in propofol doseresponse curve following selective brain CYP2B manipulation.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, we have shown in a human neuronal cell line that toxicity following 1-methyl-4-phenylpyridinum was increased with the inhibition of CYP2D, an enzyme that can metabolically inactive this potent neurotoxin (Mann and Tyndale, 2010). Recent findings have also suggested a role for brain CYPs in altering the drug-hormone cross-talk in the brain, and found that neuroactive drugs that induce brain CYPs are associated with alterations in the side-effect profiles of these drugs and, in some cases exacerbate, the disease condition (Meyer and Gehlhaus, 2010).…”

Section: Discussionmentioning

confidence: 99%

Drug Metabolism within the Brain Changes Drug Response: Selective Manipulation of Brain CYP2B Alters Propofol Effects

Khokhar

Tyndale

2010

Neuropsychopharmacol

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Drug-metabolizing cytochrome P450 (CYPs) enzymes are expressed in the liver, as well as in extrahepatic tissues such as the brain. Here we show for the first time that drug metabolism by a CYP within the brain, illustrated using CYP2B and the anesthetic propofol (2, 6-diisopropylphenol, Diprivan), can meaningfully alter the pharmacological response to a CNS acting drug. CYP2B is expressed in the brains of animals and humans, and this CYP isoform is able to metabolize centrally acting substrates such as propofol, ecstasy, and serotonin. Rats were given intracerebroventricularly (i.c.v.) injections of vehicle, C8-xanthate, or 8-methoxypsoralen (CYP2B mechanism-based inhibitors) and then tested for sleep time following propofol (80 mg/kg intraperitoneally). Both inhibitors significantly increased sleep-time (1.8- to 2-fold) and brain propofol levels, while having no effect on plasma propofol levels. Seven days of nicotine treatment can induce the expression of brain, but not hepatic, CYP2B, and this induction reduced propofol sleep times by 2.5-fold. This reduction was reversed in a dose-dependent manner by i.c.v. injections of inhibitor. Sleep times correlated with brain (r=0.76, P=0.0009), but not plasma (r=0.24, P=0.39) propofol concentrations. Inhibitor treatments increased brain, but not plasma, propofol levels, and had no effect on hepatic enzyme activity. These data indicate that brain CYP2B can metabolize neuroactive substrates (eg, propofol) and can alter their pharmacological response. This has wider implications for localized CYP-mediated metabolism of drugs, neurotransmitters, and neurotoxins within the brain by this highly variable enzyme family and other CYP subfamilies expressed in the brain.

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A role for CYP in the drug–hormone crosstalk of the brain

Abstract: The drug-hormone crosstalk may be of considerable importance in the assessment of neuroactive drugs and future drug design.

Cited by 7 publications

References 110 publications

Monocrotophos Induces the Expression and Activity of Xenobiotic Metabolizing Enzymes in Pre-Sensitized Cultured Human Brain Cells

Monocrotophos Induces the Expression and Activity of Xenobiotic Metabolizing Enzymes in Pre-Sensitized Cultured Human Brain Cells

Differential Expression of Human Cytochrome P450 Enzymes from the CYP3A Subfamily in the Brains of Alcoholic Subjects and Drug-Free Controls

Drug Metabolism within the Brain Changes Drug Response: Selective Manipulation of Brain CYP2B Alters Propofol Effects

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