Effect of ethanol on cytochrome P450 in the rat brain.

Warner, Margaret; Gustafsson, Jan‐Åke

doi:10.1073/pnas.91.3.1019

Cited by 110 publications

(77 citation statements)

References 41 publications

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“…Ethanol is metabolized to acetaldehyde mainly by the alcohol dehydrogenase pathway both peripherally and in the brain (Raskin and Sokoloff 1970) and, to a lesser extent, by oxidation through the microsomal inducible isoenzyme CYP2D1 (Warner and Gustafsson 1994) and the catalase-H 2 O 2 system (Aragon et al 1992). Acetaldehyde is subsequently transformed to acetate by aldehyde dehydrogenase.…”

Section: Discussionmentioning

confidence: 99%

Binge ethanol administration enhances the MDMA-induced long-term 5-HT neurotoxicity in rat brain

et al. 2006

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Rationale Ecstasy abuse commonly occurs in hot, overcrowded environments in combination with alcohol. Around 90% of ecstasy users take ethanol; over 70% of these users also often drink alcohol at hazardous levels. Objectives We wished to examine whether binge ethanol administration enhanced the long-lasting 5-HT neurotoxicity induced by 3,4-methylenedioxymethamphetamine (MDMA) in rats maintained at high ambient temperature and the role of acetaldehyde. Materials and methods Rats were treated with a 4-day ethanol regimen leading to plasma ethanol levels of around 450 mg/dl. On day 5, rats were placed at 30°C and administered MDMA (5 mg/kg). Rectal temperature and hydroxyl radical formation were measured immediately before and up to 6 h after MDMA. 5-HT concentration and 5-HT transporter density were determined 7 days later. A group of rats received cyanamide (50 mg/kg) on days 1 and 3 of the 4-day-ethanol inhalation. Results In ethanol treated rats, MDMA produced a hyperthermic response similar to that observed in controls but enhanced the loss of 5-HT concentration and 5-HT transporter density in the hippocampus. Cyanamide elevated the plasma acetaldehyde concentration fivefold to sevenfold, reduced the MDMA-induced hyperthermia and increased the neuronal damage with neurotoxicity also appearing in the cortex. MDMA increased hydroxyl radical production in the hippocampus, the effect being more marked in rats pre-exposed to ethanol.Conclusions Binge ethanol administration enhances the MDMA-induced long-term 5-HT neurotoxicity by a mechanism not related to changes in acute hyperthermia but probably involving hydroxyl radical formation. The magnitude of this effect is more pronounced after increasing plasma acetaldehyde levels by aldehyde dehydrogenase inhibition.

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Section: Discussionmentioning

confidence: 99%

Binge ethanol administration enhances the MDMA-induced long-term 5-HT neurotoxicity in rat brain

et al. 2006

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“…The appearance of multiple forms of P450 in brain and their selective inducibility by a variety of drugs and xenobiotics have also been identified (9,(12)(13)(14). CYP2D is one of the major forms of P450 present in both rat (15) and human brain (16).…”

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confidence: 99%

A Frameshift Mutation and Alternate Splicing in Human Brain Generate a Functional Form of the Pseudogene Cytochrome P4502D7 That Demethylates Codeine to Morphine

Pai

Kommaddi

Chinta

et al. 2004

Journal of Biological Chemistry

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A frameshift mutation 138delT generates an open reading frame in the pseudogene, cytochrome P4502D7 (CYP2D7), and an alternate spliced functional transcript of CYP2D7 containing partial inclusion of intron 6 was identified in human brain but not in liver or kidney from the same individual. mRNA and protein of the brain variant CYP2D7 were detected in 6 of 12 human autopsy brains. Genotyping revealed the presence of the frameshift mutation 138delT only in those human subjects who expressed the brain variant CYP2D7. Genomic DNA analysis in normal volunteers revealed the presence of functional CYP2D7 in 4 of 8 individuals. In liver, the major organ involved in drug metabolism, a minor metabolic pathway mediated by CYP2D6 metabolizes codeine (pro-drug) to morphine (active drug), whereas norcodeine is the major metabolite. In contrast, when expressed in Neuro2a cells, brain variant CYP2D7 metabolized codeine to morphine with greater efficiency compared with the corresponding activity in cells expressing CYP2D6. Morphine binds to -opioid receptors in certain regions of the central nervous system, such as periaqueductal gray, and produces pain relief. The brain variant CYP2D7 and -opioid receptor colocalize in neurons of the periaqueductal gray area in human brain, indicating that metabolism of codeine to morphine could occur at the site of opioid action. Histiospecific isoforms of P450 generated by alternate splicing, which mediate selective metabolism of pro-drugs within tissues, particularly the brain, to generate active drugs may play an important role in drug action and provide newer insights into the genetics of metabolism.Cytochrome P450 (EC 1.14.14.1; P450) 1 and associated monooxygenases, a family of heme proteins, are the principal class of drug-metabolizing enzymes. A supergene family encodes them, and the member proteins exist as multiple forms having distinct yet overlapping substrate specificities. Multiple forms of P450, which are selectively induced or inhibited by a variety of drugs, are known to exist in liver, the major organ involved in P450-mediated metabolism (1). However, the potential to generate active metabolite(s) at the site of action has generated interest in extrahepatic P450. This has prompted extensive investigations into the xenobiotic metabolizing capability of extrahepatic organs, such as lung, kidney, skin, and nasal epithelium, and the far reaching consequences of such metabolism, in situ, within specific cells in target organs have been recognized in laboratory animals (2) and humans (3). The preferential localization of drug-metabolizing enzymes within specific cell types in these organs renders such cells significantly capable of metabolizing drugs (4). Thus, even minor metabolic pathways of xenobiotic metabolism can produce major effects if they take place at the site of action. These observations have prompted investigation into P450-associated monooxygenases in brain with an effort to determine the capability of the brain to metabolize psychoactive drugs (5, 6). P450-mediated ...

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“…First of all, the role of ADH in the brain ethanol metabolism remains unclear, since although the presence of brain ADH has been observed, it has been reported that ethanol is not a good substrate in this organ (Beisswenger et al, 1985;Kerr et al, 1989). Other studies have shown an increase in cytochrome P450 in the brains of rats treated with ethanol (Warner & Gustafsson, 1994), observing induction of nerve cells and support cells due to the action of ethanol in the cerebellum, cerebral cortex, thalamus and hippocampus (Sohda et al, 1993;Tindberg & Ingelman-Sundberg, 1996;Upadhya et al, 2000). Additionally, Zimatkin et al (2006) reinforced in rats and mice the possibility that cytochrome P450 is involved in the brain ethanol metabolism.…”

Section: Introductionmentioning

confidence: 97%

Ethanol Intake and Toxicity: In Search of New Treatments

et al. 2017

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SANDOVAL, C.; VÁSQUEZ, B.; MANDARIM-DE-LACERDA, C. & DEL SOL, M.Ethanol intake and toxicity: In search of new treatments. Int. J. Morphol., 35(3):942-949, 2017. SUMMARY:Prolonged alcohol consumption has consequences on the liver, producing necrotic precipitates and fibrosis, on the pancreas, causing the pancreatic acini to atrophy and destroying insulin-producing cells, and on the central nervous system (CNS), causing the gray and white matter in the frontal lobes of the brain and cerebellum to atrophy. Generally, alcohol is metabolized via oxidative pathways, where the enzymes alcohol dehydrogenase and aldehyde dehydrogenase participate during its metabolization in the liver and CNS, or via nonoxidative pathways during its metabolization in the pancreas. Ethanol metabolism can produce oxidative stress and tissue damage mediated by free radicals, causing morphological and functional alterations in the liver. In the pancreas, it can cause progressive and irreversible damage affecting the endocrine and exocrine functions, a result of the activation of the stellate cells, which are activated directly by alcohol, causing pancreatic fibrosis. In the CNS ethanol can bind directly to proteins, nucleic acids and phospholipids to develop its pathogenesis. The effects produced by alcohol can be counteracted by supplementation with antioxidants, which reduce the inflammation and areas of focal necrosis in the liver, inhibit the activation of pancreatic stellate cells, and reduce oxidative stress in the CNS. Additionally, in order to reduce the negative effects associated with alcohol consumption, recent studies have suggested the administration of antioxidants as a treatment strategy.

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Effect of ethanol on cytochrome P450 in the rat brain.

Cited by 110 publications

References 41 publications

Binge ethanol administration enhances the MDMA-induced long-term 5-HT neurotoxicity in rat brain

Binge ethanol administration enhances the MDMA-induced long-term 5-HT neurotoxicity in rat brain

A Frameshift Mutation and Alternate Splicing in Human Brain Generate a Functional Form of the Pseudogene Cytochrome P4502D7 That Demethylates Codeine to Morphine

Ethanol Intake and Toxicity: In Search of New Treatments

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