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The distribution of ethanol throughout the body is driven in direct proportion to water content of each tissue, especially at the ethanol steady-state. The variation in the distribution volume of ethanol has been evaluated for women and men, and in both sexes, the distribution volume decreases as the body mass index increases [ 79 ]. Alcohol-driven physiological changes, such as vascular effects vasodilation or changes in cardiac output, can also modify tissue blood flow and ethanol distribution [ 78 ].

Since the blood flow to the brain remains relatively constant, changes in the blood concentration of ethanol are the most relevant factor influencing the amount of ethanol delivered to the brain and therefore for the different levels of brain intoxication [ 78 — 80 ]. The elimination of ethanol by the fetus is impaired due to its reduced metabolic capacity.

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Thus, fetal exposure is prolonged through the reuptake of amniotic-fluid containing ethanol [ 81 ]. Ultimately, the elimination of alcohol from the fetus relies on the mother's metabolic capacity, which inevitably is a process that occurs late, meaning that the fetus is exposed to the toxicological effects of alcohol [ 82 ].

Therefore, many of the physical effects of ethanol on brain structure not only affect neurobehavioral features during fetal development but may also persist into childhood, potentially enduring until adulthood [ 82 , 83 ]. Ethanol can cross the blood-brain barrier and it can be metabolized in the brain. Indeed, ethanol has been found in the human brain after alcohol intake [ 84 ], although metabolites of ethanol, like acetate, can also reach the brain as products of first pass metabolism [ 85 ].

Recently, the metabolism of [2- 13 C]-ethanol was evaluated in the brains of rats, and products such as labeled acetate, glutamate, glutamine, and GABA were detected found [ 86 ]. The main pathway to metabolize ethanol in the liver is that involving ADH, although it has not been definitively shown to play a role in ethanol metabolism in the brain. In certain regions of the adult rat, mouse, and human brain it has been possible to identify ADH mRNA transcripts, with ADH1 and ADH4 expressed at distinct sites [ 87 , 88 ], yet with no detectable activity after exposure to ethanol.

Nonetheless, ADH4 inhibition avoids the synaptic dysfunction associated with severe alcohol intoxication in the hippocampus [ 89 ].

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In addition, and despite fulfilling a less prominent role in ethanol metabolism [ 85 , 91 ], ADHs have been related to enhanced voluntary alcohol intake in rats [ 92 ]. Other pathways metabolize ethanol in the brain. Catalase and CYP2E1 are the main pathways; there is evidence that they do indeed play an important role in ethanol oxidation to acetaldehyde in the brain [ 91 ]. Indeed, acetaldehyde production in the brain in vivo depends on catalase activity [ 85 , 93 ] and catalase appears to be expressed in all neural cells.

Peroxisomal catalase is a tetrameric, heme-containing enzyme that, in addition to converting hydrogen peroxide H 2 O 2 to water and oxygen, can also oxidize ethanol to acetaldehyde.


The discovery of the catalase pathway for acetaldehyde formation in the brain represented an important first step in our understanding of the role of acetaldehyde in the effects of ethanol in the brain [ 94 ]. Studies using inhibitors of catalase and acatalasemic mice revealed that catalase is responsible for approximately half of the ethanol metabolism occurring in the CNS [ 91 ]. Indeed, inhibitors of catalase are also effective in inhibiting the production of acetaldehyde. The cytochrome P enzymes CYP2E1 that are involved in ethanol metabolism in the liver have also been implicated in its metabolism in the brain.

CYP2E1 reduces molecular oxygen to water and thus ethanol is oxidized to acetaldehyde. This enzyme is induced in response to chronic drinking and it may contribute to the increased rates of ethanol elimination in heavy drinkers. Some endogenous substrates for CYP2E1 include acetone and fatty acids, both of which are abundant in the brain [ 95 ]. Not only ethanol but many other substrates are also metabolized by CYP2E1, including neurotoxins or procarcinogens, producing reactive intermediates [ 97 , 98 ].

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Therefore, CYP2E1 and catalase are the main pathways in the brain that metabolize ethanol to acetaldehyde, while ADH appears to play a minor role. Acetaldehyde is a biologically active compound and it has been implicated in alcohol addiction [ , ], as well as inducing euphoria at low concentrations [ ]. The effects of ethanol are modulated by acetaldehyde [ , ], which in turn may react with endogenous substances to form other biologically active compounds.

Acetaldehydes along with other proteins adducts were found in mice brain after alcohol consumption and in alcoholic human brains, suggesting they are involved in neural damage [ , ]. Moreover adducts like salsolinol formed when acetaldehyde binds to dopamine were also seen to be involved in neurotoxicity [ ] and in reinforcing addictive ethanol conduct [ ]. Salsolinol has been identified in the brain and cerebrospinal fluid of patients with Parkinson disease, and it has been proposed to increase ROS production along with a reduction of glutathione [ ], as well as reducing intracellular ATP and thereby acting as an inhibitor of mitochondrial energy supply.

Thus, acetaldehyde reinforces its own effects or enhances the addictive action of ethanol [ , ]. As a result, acetaldehyde oxidation is required for detoxification and it can be metabolized to acetate by ALDH [ ]. Moreover, although ALDH activity has beneficial effects, such as in the reduction of acetaldehyde, it also produces free radicals. Finally, the acetate produced by ALDH is metabolized in the Krebs cycle to produce energy or provide intermediaries for other molecules. Recent research showed that oxidation of [13]C-acetate generates specific neurotransmitters, as [13]C-glutamine, glutamate, and GABA levels were higher in chronic ethanol-exposed rats than in controls [ 86 ].

The production of these molecules may be related to the known effects of GABA receptors [ 16 , 17 , 19 , ], although other receptors are also involved in the effects of ethanol, such as dopamine, acetylcholine, and NMDA receptors [ — ] Figure 2. Enzymes related to ethanol metabolism in the brain and their principal role.

Note the importance of acetaldehyde in ethanol metabolism. ROS are produced by exposure to ethanol [ 85 ] and they are associated with the effects of ethanol in the brain [ 92 , 99 , , — ], where ROS-related damage is due to oxidative stress [ 99 , , — ]. The oxidative balance is a result of the amount of ROS that accumulates and the activity of antioxidant enzymes.

In the brain, antioxidant enzymes are present in the cortex, cerebellum, hypothalamus, striatum, and spinal cord, and they include glutathione peroxidase, superoxide dismutase, glutathione reductase, and peroxiredoxin [ ]. When the oxidative balance is disturbed, oxidative stress develops that affects the cell as a whole, as well as proteins, lipids, and DNA individually, provoking neurotoxicity or neurodegeneration.

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The formation of ROS accompanies many physiological processes, such that the body has developed a system of antioxidant protection against their harmful effects. In the brain, where the generation of free radicals is particularly severe, it is essential that the antioxidant system functions correctly [ ]. Antioxidant activity is considered as enzymatic or nonenzymatic based on the mechanism of action involved. It is an enzyme that catalyzes the dismutation of the superoxide anion to hydrogen peroxide, which is then decomposed by catalases primarily located in the peroxisomes.

Increased SOD activity is considered to be an adaptive response to oxidative stress, such as that induced by acute ethanol toxicity in the cerebral cortex [ ]. However, acute ethanol intoxication reduces the activity of Cu, Zn-SOD in the cytosolic and microsomal fraction of the rat brain, and Mn-SOD activity in the mitochondria [ ]. SOD interacts closely with catalase, which catalyzes the deprotonation of peroxide hydrogen and the oxidation of substances like methanol, ethanol, formate, nitrite, and quinones.

In mammals, catalase is primarily located in the liver, erythrocytes, kidneys, and CNS. In the CNS, it can be found in microsomes [ ] and it has been shown that, in acute ethanol poisoning, there is an increase of catalase activity in the cytosol, microsomes, and synaptosomes, as well as a reduction in the mitochondria of the rat CNS [ ]. The increase in catalase activity following ethanol intake and its effects in the CNS are associated with weak ADH activity.

This increase in catalase activity in the CNS may be adaptive processes induced by the increase in the hydrogen peroxide generated, as what occurs in the CNS of animals exposed to high concentrations of ethanol [ ]. It is present in many tissues, as well as in the neurons and glia of the CNS [ , ]. The role of GSH-Px is limited to the reduction of peroxides in which glutathione participates, which is accompanied by the formation of glutathione disulfide. In the rat and human CNS, the greatest glutathione peroxidase activity is observed in the gray and white matter of the cerebral cortex [ , ].

It is an enzyme present in the cytosol and in the mitochondria of most cells, catalyzing the regeneration of reduced glutathione oxidation at the expense of NADPH.

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Most GRed activity is found in neurons and glial cells [ ], and acute ethanol poisoning significantly dampens GRed activity in the cerebral cortex [ ]. The activity of antioxidant enzymes is significantly altered in the CNS of animals chronically intoxicated with ethanol. The antioxidative capacity of the CNS also depends on exogenous antioxidants obtained by the organism through its dietary intake. The most important exogenous antioxidant in the CNS is vitamin E, and both vitamin E and vitamin C content in the CNS falls after ethanol consumption, whereas vitamin A content increases [ ].

Lipid peroxidation affects polyunsaturated fatty acids in membrane phospholipids as oxidative stress increases, producing bioactive aldehydes like 4-hydroxyalkenals and malondialdehyde [ ]. Oxidative stress and the products of lipid peroxidation, 4-hydroxynonenal HNE [ 99 , — ] or malondialdehyde [ , , ], have been related to decreased neuronal viability in some studies.

Ethanol-induced lipoperoxidation by oxidative stress [ ] and its products decrease the intracellular reduced glutathione and increase its oxidized form [ ]. HNE has also been associated with increases in mitochondrial permeability and cytochrome c release [ , , ], the latter triggering apoptotic cell death by activating caspases [ , ]. Interestingly, the toxicity mediated by the product of lipoperoxidation was weaker when glutathione transferase A activity was enhanced and glutathionyl-HNE was produced, avoiding the accumulation of HNE [ , ] and possibly serving as a mechanism of tolerance.

However, the activation of glutathione transferase A was suppressed in the presence of anionic phospholipids like cardiolipin [ ]. Cardiolipin is a phospholipid and it is the major component of mitochondrial membranes, although ethanol-induced oxidative stress provokes a loss of this lipid [ , — ] in conjunction with the appearance of HNE [ , ].

Therefore, cardiolipin oxidation occurs following ethanol ingestion and consequently its fatty acids are released from phospholipids by PLA2.

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  • When cardiolipin is affected by ethanol, mitochondrial function is impaired and the outer mitochondrial membrane may disintegrate [ , ], which could induce the release of cytochrome c from the mitochondria and trigger an apoptotic cascade mediated by caspases [ , ]. Interestingly, the neurodegeneration induced by ethanol can be prevented by an inhibitor of PLA2 in vitro [ , ].

    Phosphatidylserine PS has also been shown to play a role in apoptotic signaling, and both the reduction in PS and the enhanced neuronal cell death that ensues during the developmental period may contribute to the brain defects often observed in fetal alcohol syndrome [ ]. Ceramides are produced in the central nervous system by de novo synthesis or sphingomyelin hydrolysis [ ]. Ceramide has been shown to accumulate in mitochondria upon the induction of apoptotic processes related to neurodegeneration [ — ].

    The expression of serine palmitoyltransferase was localized in neurons and it was enhanced in caspase 3-positive neurons induced by ethanol [ ], indicating that de novo ceramide synthesis participates in ethanol-induced apoptotic neurodegeneration in the brain. Although ceramide synthase 6 CerS6 fulfills a protective role, this enzyme produces Cceramides and they are the precursors of other sphingolipids, such as sphingomyelin and glucosylceramide.

    Interestingly, CerS6 is enhanced within hours of ethanol withdrawal as a compensatory effect [ ]. In summary, ceramide is an apoptotic signal [ ] but it is also necessary for the sphingomyelin synthesis required to produce diacylglycerol DAG , which in turn activates PKC [ ], thereby avoiding apoptosis [ ]. While some lipids are altered to signal cells for destruction, others seem to offset some of the effects that occur due to oxidation. For example, there is more cholesterol in neuron membranes exposed to ethanol [ ].

    Cholesterol is known to provide rigidity to membranes and ethanol is effective in disrupting unstable lipid membranes. Hence, an increase in the cholesterol present in membranes may represent a compensatory mechanism to combat ethanol damage.