Cytochrome P450 Cyp4x1 is a major P450 protein in mouse brain

Al-anizy, Mohammed Mashog; Horley, Neill; Kuo, C.-W. S.; Gillett, Lorna C.; Laughton, Charles A.; Kendall, David A.; Barrett, David A.; Parker, Terry L.; Bell, David R.

doi:10.1111/j.1742-4658.2006.05119.x

Cited by 27 publications

(27 citation statements)

References 46 publications

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“…1C) vehicle controls. The liver expressed CYP2B10, 3A11, 1A2, and 2S1, but not CYP4X1, which is consistent with previous reports of brain-specific CYP4X1 expression in , 2006;Renaud et al, 2011). P450 expression profiles in the brain were region-specific: all five P450 isoforms were expressed in the hippocampus; the cerebellum expressed transcripts for all but CYP1A2, and the cortex expressed only CYP2S1 and CYP4X1 mRNA (Fig.…”

supporting

confidence: 80%

“…CYP2S1 is abundantly expressed in many extrahepatic tissues (Choudhary et al, 2003) and CYP4X1 is predominantly expressed in the rodent brain (Bylund et al, 2002;Al-Anizy et al, 2006). The data reported herein demonstrate brain region-specific expression of P450s in the rodent brain that is sex-and species-dependent and generally not altered by the classic inducers phenobarbital and dexamethasone under conditions that significantly induce P450 expression in the liver.…”

Section: Downloaded Frommentioning

confidence: 53%

“…We studied CYP2B (mouse CYP2B10/rat CYP2B1/2), CYP3A (mouse CYP3A11/rat CYP3A2), and CYP1A2 because these isoforms have been implicated in the metabolism of polychlorinated biphenyls (Kania-Korwel et al, 2008Curran et al, 2011), polybrominated diphenyl ethers (Erratico et al, 2013;Feo et al, 2013), and organophosphorus pesticides (Tang et al, 2001;Foxenberg et al, 2007). Two orphan P450s, CYP4X1 and CYP2S1 (Guengerich et al, 2010), were also included in this study because CYP2S1 is abundantly expressed in many extrahepatic tissues (Choudhary et al, 2003) and CYP4X1 is predominantly expressed in the rodent brain (Bylund et al, 2002;Al-Anizy et al, 2006). The data reported herein demonstrate brain region-specific expression of P450s in the rodent brain that is sex-and species-dependent and generally not altered by the classic inducers phenobarbital and dexamethasone under conditions that significantly induce P450 expression in the liver.…”

Section: Introductionmentioning

confidence: 99%

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Cytochrome P450 mRNA Expression in the Rodent Brain: Species-, Sex-, and Region-Dependent Differences

Stamou

Kania-Korwel

et al. 2013

Drug Metab Dispos

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Cytochrome P450 (P450) enzymes play a critical role in the activation and detoxication of many neurotoxic chemicals. Although research has largely focused on P450-mediated metabolism in the liver, emerging evidence suggests that brain P450s influence neurotoxicity by modulating local metabolite levels. As a first step toward better understanding the relative role of brain P450s in determining neurotoxic outcome, we characterized mRNA expression of specific P450 isoforms in the rodent brain. Adult mice (male and female) and rats (male) were treated with vehicle, phenobarbital, or dexamethasone. Transcripts for CYP2B, CYP3A, CYP1A2, and the orphan CYP4X1 and CYP2S1 were quantified in the liver, hippocampus, cortex, and cerebellum by quantitative (real-time) polymerase chain reaction. These P450s were all detected in the liver with the exception of CYP4X1, which was detected in rat but not mouse liver. P450 expression profiles in the brain varied regionally. With the exception of the hippocampus, there were no sex differences in regional brain P450 expression profiles in mice; however, there were marked species differences. In the liver, phenobarbital induced CYP2B expression in both species. Dexamethasone induced hepatic CYP2B and CYP3A in mice but not rats. In contrast, brain P450s did not respond to these classic hepatic P450 inducers. Our findings demonstrate that P450 mRNA expression in the brain varies by region, regional brain P450 profiles vary between species, and their induction varies from that of hepatic P450s. These novel data will be useful for designing mechanistic studies to examine the relative role of P450-mediated brain metabolism in neurotoxicity. IntroductionThe cytochrome P450 (P450) superfamily is a diverse group of enzymes that catalyze the oxidative metabolism of not only endogenous substrates but also xenobiotics, including environmental contaminants of significant public health concern that target the nervous system, including polychlorinated biphenyls, polybrominated diphenyl ethers, and organophosphorus pesticides (Ariyoshi et al., 1995;Foxenberg et al., 2007;Erratico et al., 2013;Feo et al., 2013). Biotransformation of these compounds by P450s can result in bioactivation or detoxication, and the balance between these activities influences the bioeffective dose, and thus the neurotoxic outcome, following environmental exposures, as shown in studies of humans and animal models (Foxenberg et al., 2007;Curran et al., 2011;Kim et al., 2011;Crane et al., 2012;Khokhar and Tyndale, 2012).Much of the research effort to characterize P450-mediated metabolism of neurotoxic compounds has focused on the liver. However, it is now evident that P450s are expressed in a number of extrahepatic tissues, including brain (Ding and Kaminsky, 2003;Ferguson and Tyndale, 2011). Although total P450 content in the human and rodent brain is generally significantly lower than that in the liver (Warner et al., 1988;Bhamre et al., 1992;Volk et al., 1995), recent evidence from rat studies demonstrates that P45...

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supporting

confidence: 80%

Section: Downloaded Frommentioning

confidence: 53%

Section: Introductionmentioning

confidence: 99%

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Cytochrome P450 mRNA Expression in the Rodent Brain: Species-, Sex-, and Region-Dependent Differences

Stamou

Kania-Korwel

et al. 2013

Drug Metab Dispos

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“…Stamou et al (2013) previously reported that CYP4X1 mRNA is equally detectable in the rat liver and brain. Al-Anizy et al (2006) showed the selective expression of Cyp4x1 in the mouse brain, while CYP4X1 mRNA was ubiquitously expressed in adult human tissues (Choudhary et al, 2005). It is of interest that CYP4X1 catalyzes the epoxidation of anandamide, an endogenous cannabinoid, but not arachidonic acid (Stark et al, 2008).…”

Section: Resultsmentioning

confidence: 99%

Expression levels of 39 Cyp mRNAs in the mouse brain and neuroblastoma cell lines, C-1300N18 and NB2a – strong expression of Cyp1b1

Yamaori

Jiang

Maeda

et al. 2017

Fundam. Toxicol. Sci.

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-An analysis of mRNA levels of 39 Cyp enzymes in the mouse brain and neuroblastoma cell lines, C-1300N18 and NB2a was performed using a real-time reverse transcriptase-polymerase chain reaction. Relative expression levels were quantified by normalized β-actin levels, and compared to the mRNA expression level of the cannabinoid receptor (CB1R), which is abundantly expressed in the mouse brain. Mean 2^-ddCts of CB1R in mouse brain, C-1300N18, and NB2a cells were 1.043, 1.003, and 1.005, respectively. Among Cyp mRNAs in the mouse brain, Cyp1b1 mRNA was the most abundantly expressed (2^-ddCt = 0.310), followed by Cyp46a1 mRNA (0.246). The other Cyp mRNAs moderately expressed (0.011 ~ 0.117) were Cyp1a1, 1a2, 2b10, 2c29, 2c50, 2d9, 2d10, 2d12, 2d22, 2d26, 3a11, 3a41, 4f14, 4f15, 4f16, and 4x1. On the other hand, 10 out of 39 Cyp mRNAs (Cyp 2b9, 2b13, 2b19, 2c37, 2c38, 2c55, 3a44, 4a12, 4a14, and 4f18) were not detectable (2^-ddCt < 0.001). In the neuroblastoma cell lines, C-1300N18 and NB2a, Cyp1b1 mRNA was also the most abundant and preferentially expressed, and relative expression levels to CB1R were 4.674 and 5.084, respectively. Thirteen other Cyp mRNAs (Cyp1a1, 1a2, 2a5, 2b10, 2c44, 2c50, 2c55, 2d10, 2d22, 3a11, 4f13, 4f15, and 4f16) were detected in the neuroblastoma cell lines, whereas 17 Cyp mRNAs (Cyp2c29, 2c37, 2c39, 2c40, 2d12, 2d34, 2e1, 3a16, 3a25, 3a41, 3a44, 4a10, 4a12, 4a14, 4f14, 4x1, and 46a1) were not under the current conditions. The pattern of Cyp mRNA expression was similar for both neuroblastoma cell lines. The present results provide fundamental and useful information on the significance of particular Cyp enzymes in the mouse brain and neuroblastoma cell lines, C-1300N18 and NB2a, which may be valuable tools for investigations on the neural expression and function of Cyp1b1.

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“…Two isoforms, CYP1A1 and CYP4X1 (Al-Anizy et al, 2006), were detected in the microsomal fraction by immunoblotting (Fig. 8, D and E).…”

Section: Inhibition Of Heme Synthesis Promptly Reducedmentioning

confidence: 99%

Early Failure ofN-Methyl-d-aspartate Receptors and Deficient Spine Formation Induced by Reduction of Regulatory Heme in Neurons

Chernova

Steinert²,

Richards³

et al. 2011

Mol Pharmacol

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An initial stage of many neurodegenerative processes is associated with compromised synaptic function and precedes synapse loss, neurite fragmentation, and neuronal death. We showed previously that deficiency of heme, regulating many proteins of pharmacological importance, causes neurodegeneration of primary cortical neurons via N-methyl-D-aspartate receptor (NMDAR)-dependent suppression of the extracellular signal-regulated kinase 1/2 pathway. Here, we asked whether the reduction of heme causes synaptic perturbation before neurite fragmentation in neuronal cultures and investigated molecular mechanisms of synaptic dysfunction in these cells. We showed the change in the NR2B subunit phosphorylation that correlates with compromised NMDAR function after the reduction of regulatory heme and a rapid rescue of NR2B phosphorylation and NMDAR function by exogenous heme. Electrophysiological recordings demonstrated diminished NMDAR currents and NMDAR-mediated calcium influx after 24 h of inhibition of heme synthesis. These effects were reversed by treatment with heme; however, inhibition of the Src family kinases abolished the rescue effect of heme on NMDA-evoked currents. Diminished NMDAR current and Ca 2ϩ influx resulted in suppressed cGMP production and impairment of spine formation. Exogenous heme exerted rescue effects on NR2B tyrosine phosphorylation and NMDA-evoked currents within minutes, suggesting direct interactions within the NMDAR complex. These synaptic changes after inhibition of heme synthesis occurred at this stage without apparent dysfunction of major hemoproteins. We conclude that regulatory heme is necessary in maintaining NR2B phosphorylation and NMDAR function. NMDAR failure occurs before neurite fragmentation and may be a causal factor in neurodegeneration; this could suggest a route for an early pharmacological intervention.

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Cytochrome P450 Cyp4x1 is a major P450 protein in mouse brain

Cited by 27 publications

References 46 publications

Cytochrome P450 mRNA Expression in the Rodent Brain: Species-, Sex-, and Region-Dependent Differences

Cytochrome P450 mRNA Expression in the Rodent Brain: Species-, Sex-, and Region-Dependent Differences

Expression levels of 39 Cyp mRNAs in the mouse brain and neuroblastoma cell lines, C-1300N18 and NB2a – strong expression of Cyp1b1

Early Failure ofN-Methyl-d-aspartate Receptors and Deficient Spine Formation Induced by Reduction of Regulatory Heme in Neurons

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