Differences in sensitivity of cultured rat brain neuronal and glial cytochrome P450 2E1 to ethanol

Kapoor, Nidhi; Pant, Aditya B.; Dhawan, Alok; Dwievedi, Uppendra N.; Gupta, Yogendra Kumar; Seth, Prahlad K.; Parmar, Devendra

doi:10.1016/j.lfs.2006.04.023

Cited by 37 publications

(41 citation statements)

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“…These cells exhibit relatively twofold higher activity of NDMA-d when compared with the liver enzyme (Kapoor et al 2006 ) . Pretreatment with ethanol reveals a signi fi cant time and concentration dependent induction in NDMA-d activity in both cell types (Kapoor et al 2006 ) . Signi fi cant induction of CYP2E1 protein and mRNA occurs in the cultured brain cells (Kapoor et al 2006 ) .…”

Section: In Vitro Evidence For Brain Cyp2e1mentioning

confidence: 94%

“…Further, chronic alcohol consumption induces liver injury in Cu, Zn-superoxide dismutase-de fi cient mice (Sod1−/−), with extensive centrilobular necrosis, in fl ammation and mitochondrial dysfunction (Kessova and Cederbaum 2007 ) . Garro et al ( 1981 ) , Arinç et al ( 2007 ) , Ma et al ( 1991 ) , Dey et al ( 2002Dey et al ( , 2005 , Kapoor et al ( 2006 ) , Khan et al ( 2011) , Anandatheerthavarada et al ( 1993 , Bhagwat et al ( 1995 ) , Huan and Koop ( 1999 ) , Roberts et al ( 1995 ) , and Zaluzny et al ( 1990 ) N-methyl formamide Lerche et al ( 1996) Diethylnitrosamine Lerche et al ( 1996) Nicotine Howard et al ( 2001 Regulation of Hepatic CYP2E1 Mediated by Pathophysiological Conditions Such as Obesity, Diabetes and Chemical Inducers Treatment of rats with the chemical inducer-4-methylpyrazole and streptozotocin which is commonly used to induce diabetes, increases CYP2E1 protein and catalytic activity and the values are additive for each inducer alone suggesting that diabetes may increase the susceptibility to toxins which are activated by CYP2E1, more so if pre-exposure to chemical inducers similar to 4-methylpyrazole, e.g., ethanol, isoniazid occurs (Wu and Cederbaum 1993a ) . Pyrazole and 4-methylpyrazole, inducers for hepatic CYP2E1 induce renal CYP2E1, through a post-transcriptional mechanism-possibly involving increased protein stabilization .…”

Section: Antioxidant Depletion Promotes Cyp2e1 Mediated Liver Injury:mentioning

confidence: 99%

“…The expression and catalytic activity of the constitutive and inducible forms of CYP2E1 in cultured rat brain neuronal and glial cells has been characterized (Kapoor et al 2006 ) . These cells exhibit relatively twofold higher activity of NDMA-d when compared with the liver enzyme (Kapoor et al 2006 ) .…”

Section: In Vitro Evidence For Brain Cyp2e1mentioning

confidence: 99%

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Cytochrome P450 2E1: Its Clinical Aspects and a Brief Perspective on the Current Research Scenario

Dey

2013

Subcellular Biochemistry

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Research on Cytochrome P450 2E1 (CYP2E1), a key enzyme in alcohol metabolism has been very well documented in literature. Besides the involvement of CYP2E1 in alcohol metabolism as illustrated through the studies discussed in the chapter, recent studies have thrown light on several other aspects of CYP2E1 i.e. its extrahepatic expression, its involvement in several diseases and pathophysiological conditions; and CYP2E1 mediated carcinogenesis and modulation of drug efficacy. Studies involving these interesting facets of CYP2E1 have been discussed in the chapter focusing on the recent observations or ongoing studies illustrating the crucial role of CYP2E1 in disease development and drug metabolism.

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Section: In Vitro Evidence For Brain Cyp2e1mentioning

confidence: 94%

Section: Antioxidant Depletion Promotes Cyp2e1 Mediated Liver Injury:mentioning

confidence: 99%

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Cytochrome P450 2E1: Its Clinical Aspects and a Brief Perspective on the Current Research Scenario

Dey

2013

Subcellular Biochemistry

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“…Proteins were extracted from primary neurons using NP-40 lysis buffer (1% NP-40, 20 mM Tris-HCl, pH 8.0, 137 mM NaCl, 10% glycerol, 2 mM EDTA, 1 mM sodium orthovanadate, 10 g/l leupeptin, and 10 g/l aprotinin) and brief sonication. Microsomal fraction was prepared as described previously (Kapoor et al, 2006). In brief, the cells were scraped in phosphate-buffered saline and then pelleted by centrifuging at 200g for 10 min.…”

Section: Methodsmentioning

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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“…Several studies have shown that there is enzymatic activity in the brain, which can metabolize both EtOH and acetaldehyde (Brzezinski et al 1999;Upadhya et al 2000;Sun and Sun 2001;Kapoor et al 2006;Roberto et al 2006;Vasiliou et al 2006;Yadav et al 2006;Zimatkin et al 2006). Yadav et al measured NDMA-d activity in the presence and absence of alcohol (Yadav et al 2006).…”

Section: Folic Acid and Alcohol (Etoh)mentioning

confidence: 99%

FASD: folic acid and formic acid — an unholy alliance in the alcohol abusing mother

Kapur

Baber

2018

Biochem. Cell Biol.

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Alcohol consumption during pregnancy remains a significant cause of preventable birth defects and developmental disabilities; however, the mechanism of toxicity remains unclear. Methanol is present as a congener in many alcoholic beverages and is formed endogenously. Because ethanol is preferentially metabolized over methanol, it has been found in the sera and cerebro-spinal fluid of alcoholics. Toxicity resulting from methanol has been attributed to formic acid. Formic acid is present in significantly higher quantities in the biofluids of alcoholics. These higher levels can be cytotoxic and cause neuronal cell death. However, the adverse effects can be mitigated by adequate levels of hepatic folic acid, because formic acid elimination depends on folic acid. During pregnancy, folate concentrations are at least 2-fold higher in cord blood then in maternal blood, owing to increased folate requirements. The reverse has been demonstrated in pregnancies with alcohol abuse, suggesting downregulation of folate transporters and low fetal folate levels. Moreover, formic acid can cross the placenta and its adverse effects can be mitigated by folic acid. Thus, the combination of low fetal folate levels and presence of formic acid form a potent cytotoxic combination that may play a significant role in the etiology of fetal alcohol spectrum disorder.Key words: formic acid, methanol, folic acid, FASD, neurotoxicity.Résumé : La consommation d'alcool pendant la grossesse demeure une cause significative de déficiences congénitales et développementales évitables, mais le mécanisme responsable de sa toxicité est encore flou. Le méthanol est présent comme congénère dans plusieurs boissons alcooliques et il est formé de manière endogène. Puisque l'éthanol est préférentiellement métabolisé par rapport au méthanol, ce dernier a été trouvé dans le sérum et le liquide céphalorachidien des personnes alcooliques. La toxicité résultant du méthanol a été attribuée à l'acide formique. L'acide formique est présent en quantité significativement plus élevée dans les liquides biologiques des patients alcooliques. Ces niveaux plus élevés peuvent être cytotoxiques et causer la mort neuronale. Cependant, ces effets nocifs peuvent être atténués par des niveaux appropriés d'acide folique hépatique, car l'élimination d'acide formique dépend de l'acide folique. Durant la grossesse, les concentrations de folate sont au moins deux fois plus élevées dans le cordon ombilical que dans le sang maternel à cause des besoins accrus en folate. L'inverse a été démontré chez les femmes enceintes qui abusent d'alcool, suggérant une régulation à la baisse des transporteurs du folate et de faibles niveaux foetaux de folate. En outre, l'acide formique peut traverser le placenta et ses effets nocifs peuvent être atténués par l'acide folique. Ainsi, de faibles niveaux foetaux de folate et la présence d'acide formique forment une combinaison cytotoxique puissante qui peut jouer un rôle significatif dans l'étiologie de troubles du spectre de l'alcoolisation foet...

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Differences in sensitivity of cultured rat brain neuronal and glial cytochrome P450 2E1 to ethanol

Cited by 37 publications

References 45 publications

Cytochrome P450 2E1: Its Clinical Aspects and a Brief Perspective on the Current Research Scenario

Cytochrome P450 2E1: Its Clinical Aspects and a Brief Perspective on the Current Research Scenario

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

FASD: folic acid and formic acid — an unholy alliance in the alcohol abusing mother

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