Ethanol

Ethanol (ethyl alcohol, alcohol; molecular weight 4ft) is readily water-soluble, and has HO

a limited capacity to dissolve sliiihllv hydrophobic molecules,

Figur* 7.21 Ethanol

Abbreviations

ADH alcohol dehydrogenase

AIDH aldehyde dehydrogenase

CoA coenzyme A

FAD flavin adenine ¿¡nucleotide

FMN flavin mononucleotide

MEO microsomal ethanol oxidizing system

Nutritional summary

Function, hi Hanoi is an energy-rich nutrient thai provides about 7kcal g. Its conversion loacelyl-CoA requires riboflavin, niacin, pantothenate, zinc, (heme) iron, molybdenum, and magnesium; Further oxidation of acetyl-CoA to water and carbondioxide depends on thiamin, riboflavin, niacin, pantothenate, lipoate, ubiquinone, iron, and magnesium. The ethanol metabolite acetate can be used as a precursor for fatty acid and cholesterol synthesis,

Food sources Alcoholic beverages typically contain It) 2fl g ethanol per serving (glass of beer or wine, shot glass of liquor). Foods do not contain significant amounts of alcohol unless they are steeped in liquor. Ethanol is convened completely into acctyl-CoA which is liitle compared to the several hundred grams which are generated daily during the breakdown of carbohydrates, fat. and protein.

Requirements: No dietary ethanol intake is necessary. The beneficial effect of moderate ethanol intake (one drink or less a day) on cardiovascular risk often is outweighed by adverse effects from violent death or injury, and the potential for habitual or addicted excessive consumption.

Excessive intake: Even moderate intakes of ethanol (as little as one drink) slow response time, impair motor control, limit judgment, and thus increase the risk of accidents and perpetrating or suffering crimes. Acute poisoning with large amounts can induce coma and death. Chronic abuse can lead to dependency, increase cancer risk, induce bone loss, and cause damage to liver, heart, pancreas, brain, and other organs.

Endogenous sources

Pathological microorganisms in the small intestine (e.g., Candida albicans) can generate several grams of ethanol per day in some individuals. Normal intestinal flora can do the same when significant amounts of fermentable carbohydrates reach the terminal ileum and colon (Geertingcrcfo/., 19S2: Picot etui.. 1997; Cope eta!.. 2000). A specific syndrome due to high gastrointestinal ethanol production IVIei-Tei-Sho) has been described in Japan (Picot et aL, 1997). which may be related to high rice intake-

Dietary sources

Ethanol is consumed mostly with alcoholic beverages such as beer, wine, hard cider, liqueurs, and hard liquor. A typical serv ing of American beer (360 ml/12 fioz) contains about !3g of ethanol. The same amount of light beer has about 11 g. About lOg is consumed with a smalt glass of wine (100 ml 3.5 lloz). I6gwtrha40ml (1.5 fioz) jigger of hard liquor (whiskey, gin. vodka etc.). Very small amounts may be taken up with fruits and vegetables, especially if they are fermented. Foods steeped in alcoholic beverages (e.g. fruitcake with rum) may contain unexpectedly targe amounts depending on the recipe.

Ethanol tastes bitter to most people I Mattes and DiMeglio. 2001 >. Acute ingestion decreases quinine bitterness, but enhances its aftertaste.

Digestion and absorption

Ethanol is absorbed in the stomach and proximal small intestine. Since ethanol readily permeates lipid membranes the main transfer mechanism appears to be diffusion. The lining of mouth, esophagus, and stomach has significant capacity for the first steps of ethanol metabolism. Because of this, a small proportion of ingested ethanol is transferred into blood as acetaldehyde and acetic acid.

Transport and cellular uptake

Ethanol is readily soluble in plasma and not associated with macromoleculcs or cells. Blood concentrations are related to quantity and time since intake, but foods ingested with or prior to a dose, genetic disposition, and habituation greatly modify individual responses. Concentrations in excess of 4g/l, which would be lethal for most people, have been measured in habituated individuals alter consumption of targe amounts. Ethanol rapidly crosses both the blood brain barrier and the placenta, because it diffuses freely through cell membranes.

Metabolism

Overview. Small doses of ingested ethanol are taken up and metabolized mainly in the stomach wall (Lim eta!,, 1993; Liebcr, 2(HI0). Larger doses that exceed the first-pass metabolic capacity of the gastrointestinal wall arc metabolized in the liver. About three-quarters of a moderate dose is exported to peripheral tissues as acetate: less than 5"» contribute lo de novo lipogenests in liver iSilerw at.. 1999).

Ethanol oxidation. After consumption of moderate amounts (less than 5 lOg/day) the zinc-containing cytosolic enzyme alcohol dehydrogenase (ADM: EC I.LI.1) in the stomach and liver initiates ethanol metabolism in a NAD-dependent reaction. Several isoenzymes occur due to the formation of homo- and heterodiiners of alpha-, beta-, and gamma-chains. Four additional isoforms exist, formed as homodimers of chains from distinct genetic loci and with catalytic and other characteristics different from the lirst three dominant forms. Women have distinctly lower class 111 and IV ADH activities in stomach than men and as a consequence ethanol is metabolized less rapidly in the digestive tract lining and a higher percentage of an ingested large dose reaches circulation (Seitz etal., 1993; Baraona etui., 20011. Ai higher consumption levels and in habituated indi\ ¡duals (those consuming in excess of 5 1 drinks a week or more) ethanol is increasingly oxidized by the microsomal ethanol oxidizing system (MI-OS) which includes monooxygenases of the cytochrome P-450 family (EC 1.14.14.1) with broad specificity. CYP2E1 and. to a lesser extent, CYPIA2 and CYP3A4 arc the main cthanol-oxidi/ing enzymes of the MEOS (Salmela etai, I99S). A tlavoprotein. NADPIl-ferrihemoprotcin reductase (EC 1.6.2,4), which contains both FMN and FAD, is structurally associated with the cytochromes and uses the reducing equivalents to generate NADPH. Riboflavin deficiency in rats has been found to reduce the activity of this enzyme (Wang et a!., 1985).

X-CHa HO Acetate

Acetate CoA Ii gase H.

CoA CoA ligase

c-ch3

Aldehyde dehydrogenase

HaOj

Aldehyde oxidase (Mo cofactor, Fe2*. heme, FAD) O^HjO

iii • reauciase

/ yheme-ttiiolatejy V (FMN.'FAD)

vC-CM3

ch oh

Acetyl-CoA

3 Acetaldehyde

NADH HjO-J

Alcohol V Mk°S \/ NADPH" dehydrogenase cytochromes yfernhemoprotein

(co(actor2n"l P450 A reductase ch oh iii • reauciase

/ yheme-ttiiolatejy V (FMN.'FAD)

Ethanol

Figur* 7.22 Ethanol oxidation and formation of accryl-CoA

Acetaldehyde: The intermediate generated by ADH action can be metabolized to acetic acid mainly by two types of enzymes, aldehyde dehydrogenase (A1DH: EC 1.2.1.3/ NAD-requiriHg, EC 1.2.1.4 NADP-requiring, EC 1.2.1,5'NAD or NADP-requiring) and acetaldchvdc oxidase (ECl.2.3.1), which generates hydrogen peroxide. Many distinct gene products conforming to three different enzyme types (differing in cofactor requirement) exert A1DH activity in both cytosol and mitochondria. ALDI12 (EC 1,2.1.3) in the mitochondrial matrix of liver appears to be of particular importance for the clearance of large ethanol -derived amounts of acetaldehy de. since Orientals and South American Indians vuth an inactive variant (504E > K) have greatly increased susceptibility to acute alcohol intoxication. Other forms of AIDH are more abundantly expressed in tissues and organs of the upper digestive tract such as salivary glands, esophagus, and stomach. The cytoplasmic enzyme acetaldehyde oxidase (ECl,2.3.1) is abundantly expressed in liver; in kidney, heart, and brain a less abundant variant is produced from a shortened transcript starting at an alternative polyadenylation site (Tomita el a! IW3). This enzyme requires FAD, the molybdenum cofactor, heme, and additional irons arranged in a 2Fe-2S cluster.

When ethanol oxidation by the MEOS increases and acetaldehyde production greatly exceeds the capacity lor its oxidation, tissue concentrations may reach levels that arc directly toxic. Some individuals, especially of Asian descent, are susceptible to ethanol-induced flushing. This effect may be due to competition of acetaldehvde with the metabolites of histamine, methylimidazole acctaldehyde, and imidazole acetaldehvde (Zimatkin and Anichtchik. 1999). A single-base variant of ALDH2 increases susceptibility to alcohol-induced flushing (Crabb, 1990), Acetate: While a significant proportion of unconjugated acetate is exported from liver to muscle and other tissues (Siler et al., 1999), large amounts are conjugated in mitochondria or cytosol by acetate-Co A ligase (Ihiokmasc. ECfi.2.1.1) and metabolized via the Krebs cycle. Alternatively, acetyl-CoA may enter one of several synthetic pathways for fatty acids, cholesterol, and other compounds. Condensation of two acetyl-CoA moieties (acetyl-Co A C-acety 1 trans (erase, EC2.3.I.9), and addition of another acetyl-CoA (hydroxymethylglutaryl-CoA synthase, EC4.1.3.5) frees up twoCoA residues. The linal CoA is released through the action of HMG-CoA lyase (EC4.1.3.4). Acetoacetate can be decarboxylated non-enzymatically to acetone, or be reduced by 3-hydroxy bu-tyrate dehydrogenase (EC1.1.1.30) to beta-hydroxybutyrate. These three ketone bodies, acetone, acetoacetate. and beta-hydroxybutyrate, are exported into blood and utilized by muscles, brain, and other cxtrahepatic tissues. The oxidative capacity for ketone bodies is exceeded when their concentration in arterial blood rises above 700mg f. Such high ketone body concentrations often occur with chronic consumption of large amounts of ethanol. In this ease, noticeable amounts will appear in breath and urine. Free radicals: The metabolism of ethanol generates large amounts of oxygen free radicals. Hydrogen peroxide is produced by aldehyde oxidasc-mediated oxidation of acetaldehvde in peroxisomes; in addition, acetaldehvde oxidase (EC1.2.3.1) can give rise to superoxide radicals from NADU generated by alcohol dehydrogenase (Ntira et at, 1995). Carbon-centered radicals such as the hydroxyethyl radical can form adducts with cytochrome P450 2E1 and trigger specific autoimmune reactions associated with alcoholic liv er cirrhosis (Clot et at, 1997).

Compound drup: Users of cocaine and ethanol are exposed to a compound drug, cocaethy lcue. which arises from the in vivo transeslerilication of cocaine; eoeaethyl-ene is thought to Ik* more neurotoxic than cocaine and readily passes across the placenta (Simone et at, 1997).

Function

Energy production Ethanol has higher caloric density (6.9 kcal g) than carbohydrates or proteins. There is increasing doubt about how much of the chemical energy content of ethanol can be utilized by humans (Siler et at. 1999)

Impact on intestinal function- Ethanol consumption increases intestinal motility and may cause diarrhea. Ingestion of significant amounts may interfere w ith the intestinal absorption of amino acids, folate I Feinman and Lieber, 1994). biotin (Said et at. 1990). and other nutrients.

Metabolic effects: Excessive ethanol oxidation increases the NADH/NAD ratio in liver two- to three-fold which affects many other metabolic pathways including oxidation of ethanol itself, gluconeogenesis. fatty acid oxidation, and lipoprotein secretion At high concentrations ethanol also competes with the metabolism of many xenobiotics, including medicinal drugs. Ethanol also increases greatly the proportion of 5-hydroxytryptaniine (serotonin) that is convened into the dead-end product 5-hydroxytryptophol (5-1ITOL) by alcohol dehydrogenase (EC 1.1.1.1), enough to cause headaches, diarrhea, and fatigue in healthy subjects (Helander and Some. 2000). Toxicity. Ethanol is acutely toxic for many tissues. Even relatively small doses (less than 0.1 g- kg body weight) increase reaction lime, larger doses impair coordination, cloud judgment, and affect mood. Acute effects of large doses may also include loss of voluntary and involuntary motor control, vomiting, double vision, agitation, delusions. coma, and even death. Long-term overcon sumption can cause fatty liver, hepatitis, liver cirrhosis, pancreatitis and cirrhosis of the pancreas, and various other damages Even at relatively modest intake levels, ethanol consumption appears to increase risk of rectal and colon cancer (Sett/ et til.. 2001, Simanowski etat.. 2001), possibly also risk of cancer at other sites. Ethanol consumption during pregnancy often is responsible lor typical facial and other malformations and impaired mental development (fetal alcohol syndrome) in the children. Genetic differences in alcohol metabolism influence vulnerability of the fetus (Strcissguth and Dehaene, 1993; McCarver, 2001). Even seemingly small amounts of alcoholic beverages (one drink) have the potential for irreversible harm.

Habituation and alcoholism: Ethanol habituation induces several enzymes of the MEOS. especially cytochrome P450 2E1; induction of these enzymes greatly increases the capacity to metabolize ethanol iLieber, 1999), Oxidation of ethanol without phosphorylation by the MEOS might explain the relatively inetficient utilization of its energy, especially in habituated drinkers (Feinman and Lieber. 1994).

As a consequence of MEOS induction, acetaminophen and other commonly used drugs are metabolized more rapidly to their toxic metabolites; similarly, the accelerated activation ofdimethylnitrosaminecan promote carcinogenesis. Catabolism of retinol is also accelerated, f inally, the induction of ethanol-meiabohzing enzymes and various other liver proteins, including apolipoprotein A-1, affects synthesis and breakdow n of lipids and lipoproteins (Luoma, I98X). Thus, increased omega-hydroxylation can change both type and rate of Tally acid metabolism (Laethem et at.. 1093; Adas etat., 1998). Both beneficial and detrimental changes of lipoprotein profiles can result, depending on quantitative ethanol exposure, dietary habits, and indiv tdual disposition.

About one of ten Americans suffer from alcoholism at sometime in their lives (Garbutt et a!., 1999). Drug treatment options with a reasonable level of evidence for effectiveness include opioid antagonists (naltrexone, nalmefene). acamprosale (Garbutt ct al„ 1999), and disulfiram. Disulliram inhibits ethanol metabolism by irreversible carbamoyl at ion and inhibition of mitochondrial aldehyde dehydrogenase (Shen et a!.. 2001).

References

Adas F. Betthou F. Pican I). Lozac'h I*. Bcaugc F. Amet V. Involvement of cytochrome P450 E21 in the (omega 1 )-hydroxylation of oleic acid in human and rat liver microsomes. ./ Lipid Res I99K;39;1210 ll> Baraona E, Abittan CS, Dohinen K. Moretti M. Poz/alo G. Chaves /.W, Schaefer C, Lieber CS. Gender differences in pharmacokinetics of alcohol.. tlcofiol Clin Exp Res 2001:25:502 7

Clot P, Parola M, Bellomo G. Dianzanl U, Carim R, Ta bone M, Arico S. Ingelman-Sundberg M. Alhano Ii. Plasma membrane hydroxyethyl radical ad ducts cause antibody-dependent cytotoxicity in rat hepatocytes exposed to alcohol, Gastroenterol 1997;113:265-76

Cope K. Risby T. Diehl AM. Increased gastrointestinal ethanol production in obese mice:

implications lor fatty liver disease pathogenesis. Gastwenterol 2000:119:1340 7 Crabh DW. Biological markers for increased risk of alcoholism and for quantitation of alcohol consumption. J Clin Invest 1490:85:311-15 Feinmun L. Lieber CS. Nutrition and diet in alcoholism. In Shils ML, Olson JA, Sinke M eds. Modern Nutrition in Health and Disease. 8th edn. Lea &. Febiger, Philadelphia. PA. 1994, pp.1081-101 Garbutt JC, West SL. Carey TS, Lohr KN, Crews FT Pharmacological treatment of alcohol dependence: a review of the evidence. JAMA 1999;281:1318-25 Geertingcr P. BodcnhoffJ. Helweg-Larsen K. f und A. Endogenous alcohol production by intestinal fermentation in sudden infant death. ZRechtsmed 1982:89:167 72 He lander A. Some M. Dietary serotonin and alcohol combined may provoke adverse physiological symptoms due to 5-hydroxytryptophol. Ule Sei 2000;67:799-806 Lacthem RM. Balaxy M. Falck JR. I.aethem CL. Koop DR. Formation of 19(SK 19(RK and 18(R i-hydroxy-eicosateiraenoic acids by alcohol-inducihle cytochrome P4502EL JBhIChem |993;268:I2912 18 Lieber CS. Microsomal ethanot-oxidizing system (MEOS): the First 30 years (1968 1998)

a review. Alcoholism Clin Exp Res I999;23:99l 1007 Lieber CS, Alcohol: its metabolism and interaction with nutrients. Anna Rev \'tUr 2000; 20:395-430

Lim RT Jr, tienirv RT. Ito D. Yokpyama 11. Baraona L, Lieber CS. First-pass metabolism of ethanol is predominantly gastric. Alcohol Clin Exp Res 1993:17:1337 44 Luoma PV. Microsomal enzyme induction, lipoproteins and atherosclerosis. Pharmacol

Toxicol 1988;62:243-9 Mattes RD. DiMeglio D. Ethanol perception and ingestion. Physiol Behav 2001 ;72:217 29 McCarvcr IXi. ADH2 and CYP2EI genetic polymorphisms: risk factors for alcohol-

related birth defects. Drug Menth Disp 200l;29:562 5 Mira L, Maia L. Barrelra L. Manso CF. Evidence for free radical generation due to NADH oxidation by aldehyde oxidase during ethanol metabolism. Arch Biochem Biophys 1995;318:53-8

Pieot D, Lauvin R, llellegouarc'h R. [Intra-digcslivc fermentation in intestinal malabsorption syndromes: relations with elevated scrum activity of gamma-glut amy I-transpeptidase]. Gastroenterol Clin Bio! I997;21:562 6 Said MM. Sharifan A. Bagherzadch A, Mock D. Chronic ethanol feeding and acute ethanol exposure in vitro: effect on intestinal transport ofbiotin. ImJClin Nutr 1990:52:1083 6 Salmela KS. Kessova IG. Tsvrlov IB. Lieber CS. Respective rotes of human cytochrome P-4502E1, IA2, and 3A4 in the hepatic microsomal ethanol oxidizing system. Alcoholism: Clin Exp Res 1998;22:2125-32 Seil/ HK. Egerer G. Simanowski LA, Waldherr R, Eckey R. Aganval DP, Goedde HW, von Wartburg JP. Human gastric alcohol dehydrogenase activity: effect of age. sex, and alcoholism. Gut 1993:34:1433-7

Seil/ UK. Malsuzaki S, Yokovania A. Homann N. Vakcvainen S. Wang XD. Alcohol and cancer.Alcoholism: Clin Exp Res 2001:25:1 J7S 143S Shen ML. Johnson KL. Mays DC. l.ipsky J J, Naylor S. Determination of in vivo adducts of disulfiram with mitochondrial aldehyde dehydrogenase. Bioehem Pharmacol 2001:61:537 -15

Siler SQ. Neese RA. I lellerstein MK. De novo lipogenesis, lipid kinetics, and whole-body lipid balances in humans after acute alcohol consumption. Am J Clin Sutr 1999; 70:928-36

Simanowski UA, Homann N. Knuhl M. Arce L. Waldherr R. Conradl C. Bosch FX, Seil/ HK, Increased rectal cell proliferation following alcohol abuse. Gut 200l;49:418 22 Simone C. Byrne BM, Dcrewlany LO, <)skamp M. Koren G. The transfer of cocaethylene across the human term placental cotyledon perfused in vitro. Reprod Toxicol 1997; 11:215-19

Streissguth AP, Dehaene P. Fetal alcohol syndrome in twins of alcoholic mothers: concordance of diagnosis and 10- Am J Med Genet 1993:47:857-61 Tomita S. fsujita M. lchikawa Y. Retinal oxidase is identical to aldehyde oxidase. FF.BS Lett 1493:336:272-4

Wang T. Miller KW. Tu YY. Yang CS. Effects of riboflavin deficiency on metabolism of nitrosamines by rat liver microsomes. J Matt Cancer Inst 1985:74:1291-7 Zimatkin SM. Anichichik OV. Alcohol-histamine interactions, ih Alcoholism 1999; 34:141 7

Understanding And Treating Autism

Understanding And Treating Autism

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