Prajapati, 1___

Alcohol Metabolism and its Dependence

Prajapati, Milankumar V. Dr. Byron C. Yoburn PHM 216, Applied Psychopharmacology, Fall 2011.

INTRODUCTION
Alcohol (i.e. Ethanol) is metabolized in body by several pathways, mainly oxidative and rarely non-oxidative metabolic pathways (Schuckit M.A., 2011). The four principal oxidative enzymes responsible for elimination of alcohol are alcohol dehydrogenase (ADH), aldehyde dehydrogenase (ALDH), cytochrome P450 (CYP2E1) and catalase (Zakhari, 2006). ADH and ALDH plays pivotal role in elimination of most ethanol via oxidation to acetaldehyde and acetate. These enzymes are well-known to exhibit genetic polymorphism (Chen et al., 1999). Genetic variation of these alcohol metabolizing enzymes have been found to influence consumption of alcohol, drinking behavior (Chen et al., 1999; Zakhari, 2006). The goal of this term paper is to review the polymorphism of alcohol metabolizing enzymes and its association with drinking behavior and ultimately alcoholism.

ALCOHOL METABOLISM
Figure , Oxidative pathways of alcohol metabolism (Deitrich et al., 2006)

Prajapati, 2___ On oral ingestion, ethanol is primarily absorbed from small intestine and reaches to liver via portal vein (Schuckit M.A., 2011). Apart from primary site of metabolism of ethanol (liver), it is also metabolized in extra hepatic tissue such as stomach and brain. Cytochrome P450 and catalase are responsible for ethanol metabolism in tissue deficient ADH.(Zakhari, 2006) Metabolic pathways rendering alcohol to its byproducts are classified as oxidative and non-oxidative pathways.

Oxidative Pathways
As depicted in figure 1, sequential oxidation of alcohol by ADH (cytosol) to acetaldehyde and then to acetate by ALDH is the primary means of elimination
(Schuckit M.A., 2011).

Secondarily, Cytochrome P450 (CYP2E1, microsomes), an

inducible enzyme, contributes to alcohol metabolism at higher alcohol concentration under special condition such as alcoholism. In addition to these, catalase (peroxisome) with the help of hydrogen peroxide is capable to oxidize alcohol to acetaldehyde, but availability of hepatic hydrogen peroxide is low to support ethanol metabolism through this pathway (Schuckit M.A., 2011).

Non-oxidative Pathways
Figure , Non-oxidative pathways of alcohol metabolism (Deitrich et al., 2006)

Prajapati, 3___ Ethanol metabolism by this pathway is rare and minimal, non-oxidative

detoxification occur in two ways, first by interaction of alcohol and fatty acid to form fatty acid ethyl ester (FAEE) catalyzed by FAEE synthase. FAEE is known to produce tissue injury. Second pathway involves action of phospholipase D (PLD) to form phosphatidyl ethanol. PDL has high Km1(Zakhari,
2006)

for ethanol and reaction requires

high ethanol concentration (alcoholics are more prone).

ACETALDEHYDE AND BEHAVIORAL EFFECTS

Alcohol metabolism is important biological determinant that can influence alcohol drinking behavior and alcoholism (Chen et al., 1999; Chen et al., 2009). Acetaldehyde, first active metabolite generated after alcohol metabolism

(Quertemont and Didone, 2006), is known to exert toxic as well as pharmacological and behavioral effects of alcohol in particular alcohol abuse and alcoholism (Quertemont, 2004). However, the central effects of acetaldehyde are controversial and the hypothesis of mediating alcohols effect by acetaldehyde was not much flourished (Quertemont, 2004). Several animal studies are in favor of the hypothesis based on three study outcome (Quertemont, 2004). First, acetaldehyde has strong rewarding property (positive reinforcing) on intracerebroventricular administration in animals. Second is on association of different animal strains on acetaldehyde production and alcohol consumption. Third, variation on alcohol metabolism and its consumption. Though these outcomes are in favor of the hypothesis, some reasonably argue it. For instance, rats with lower ALDH activity shows negative relation between blood acetaldehyde level and alcohol intake by producing peripheral adverse reactions (Quertemont, 2004). Based on these observation it

1 It is the parameter of enzyme activity, which describes concentration of substrate upon which
enzyme acts that permits half of the maximum rate of reaction.

Prajapati, 4___ was hypothesized that acetaldehyde exerts its action depending on location and its accumulation within the body parts. Acetaldehyde action on brain lead to rewarding property where as its peripheral effects leads to adverse effects refraining alcohol (Quertemont and Didone, 2006).

POLYMORPHISM IN ALCOHOL METABOLISING GENE

Alcohol metabolizing enzymes (ADH, ALDH, catalase, CYP2E1) show genetic polymorphism (Chen et al., 1999). There are several allelic variants of alcohol metabolizing enzymes. Catalase is mainly responsible of metabolism of alcohol in brain (Deitrich et al., 2006) as high levels are found in various brain regions (Correa et al., 2011). Genetic variation in catalase can influence brain acetaldehyde production (Quertemont, 2004), and is associated with strong rewarding property, but role of catalase in alcohol consumption requires further investigation. The same is true for CYP2E1 polymorphism and it is believed generally that CYP2E1 polymorphism is not associated with alcoholism and drinking behavior (Quertemont, 2004). Allelic variation of two key enzymes is worth noting are ADH and ALDH as shown in table 1. Genetic variant of ADH1B (ADH1B2, ADH1B3) and ADH1C (ADH1C1) are responsible for faster metabolism of alcohol and are studied for their role in alcoholism (Quertemont, 2004). Low prevalence of ALD1B2 and ALD1C1 in alcohol dependents pin point its role in alcoholism (Chen et al., 2009). However the role of ADH1B doesnt appear significantly for acetaldehyde production (Chen et al., 2009).

Enzy me

Class

Gene Nomenclature New Forme r

Prevalence

Prajapati, 5___ ADH I ADH1A ADH1B*1 ADH1B*2 ADH1B*3 ADH1C*1 ADH1C*2 ADH1 ADH2* 1 ADH2* 2 ADH2* 3 ADH3* 1 ADH3* 2 Caucasian & American Indian2, Indian population3 East Asian2 Black population2 East Asian and Black Population2 Caucasian & American Indians equally distributed with ADH1C12

II

ADH4

ADH4

III

ADH5

ADH5

IV

ADH7

ADH7

ADH6

ADH6

ALDH

ALDH1 ALDH2*1 ALDH2*2

ALDH1 ALDH2 *1 ALDH2 *2

Asian4

2 Chen et al., 2009, 3 4

Quertemont, 2004,

Wall et al., 2003.

Prajapati, 6___ Mutation on ALDH can reduce its activity by 85% (Israel et al., 2011) in ALDH2*2 variants. Individual with these allelic forms (ADH, ALDH) will evidently protect against alcoholism. It was noted that homozygous ALDH2*2 will have full protection against alcoholism whereas heterozygous ALDH2*2 are partial protected (Chen et al., 2009). To sum up with, the key polymorphism of two ADH (ADH1B, ADH1C) on chromosome 4 and one ALDH (ALDH2*2) on chromosome 12 can influence acetaldehyde concentration intra-cellularly in general and alcohol dependence in particular (Wall et al., 2003).

Figure , Acetaldehyde production in rats (Rivera-Meza et al., 2010).

Prajapati, 7___
Table 1, ADH and ALDH Polymorphism (modified from Zakhari, 2006)

SIGNIFICANT RESEARCH FINDINGS

Prajapati, 8___ One of the important observations that I would like to add in here is the study conducted by Rivera-Meza and colleague on Wistar-derived UChB rats (Rivera-Meza et al., 2010). In the study high ethanol consuming rats were administered with adenoviral vector of mutant rat analog of human ADH1*B (rADH-47His), wild type ADH (rADH-47Arg) enzymes and empty vector (Adv-noncoding) as control. It was observed that rat analogue ADH1*B shows 90% increase in ADH activity while normal ADH shows 32% increase(Rivera-Meza higher activity et al., show 2010). high On ethanol

administration,

animal

with

will

acetaldehyde

concentration than that of control (Adv-noncoding) as shown in figure 3. The study is extended beyond the acetaldehyde production with the question that Will rise in acetaldehyde have any effect on alcohol consumption? The answer to question was found yes with evidence in figure 4 that high ADH activity will lead to more acetaldehyde production and concurrent decrease in ethanol intake. The mutant rADH-47His has higher acetaldehyde production and consume a smaller amount of alcohol than wild type rADH-47Arg when both are compared to control Adv-

Prajapati, 9___ noncoding.

Figure 4, Alcohol consumption in rats (Rivera-Meza et al., 2010).

CONCLUSION
In nutshell, genetic polymorphism of ADH and ALDH has great influence on susceptibility of alcoholism. Correlation between acetaldehyde productions after ethanol consumption and drinking behavior in animal with allelic variants play crucial role in protection against alcoholism. Role of acetaldehyde in brain is still open areas of investigation as molecular mechanisms and polymorphism is not well established. _____________________________________________________________________________________

References

Prajapati, 10___
Schuckit M.A. (2011). Chapter 23. Ethanol and Methanol. In L.L. Brunton, B.A. Chabner, B.C. Knollmann (Eds), Goodman & Gilman's The Pharmacological Basis of Therapeutics, 12e. Retrieved November 27, 2011 from http://www.accessmedicine.com/content.aspx?aID=16666094.

Chen CC, Lu RB, Chen YC, Wang MF, Chang YC, Li TK, Yin SJ. (1999) Interaction between the functional polymorphisms of the alcohol-metabolism genes in protection against alcoholism. Am J Hum Genet 65:795-807. Chen YC, Peng GS, Wang MF, Tsao TP, Yin SJ. (2009) Polymorphism of ethanolmetabolism genes and alcoholism: Correlation of allelic variations with the pharmacokinetic and pharmacodynamic consequences. Chem Biol Interact 178:2-7. Correa M, Salamone JD, Segovia KN, Pardo M, Longoni R, Spina L, Peana AT, Vinci S, Acquas E. (2011) Piecing together the puzzle of acetaldehyde as a neuroactive agent. Neurosci Biobehav Rev 36:404-430. Deitrich R, Zimatkin S, Pronko S. (2006) Oxidation of ethanol in the brain and its consequences. Alcohol Res Health 29:266-273. Israel Y, Rivera-Meza M, Quintanilla ME, Sapag A, Tampier L. (2011) Acetaldehyde burst protection of ADH1B*2 against alcoholism: An additional hormesis protection against esophageal cancers following alcohol consumption? Alcohol Clin Exp Res 35:806-810. Quertemont E. (2004) Genetic polymorphism in ethanol metabolism: Acetaldehyde contribution to alcohol abuse and alcoholism. Mol Psychiatry 9:570-581. Quertemont E and Didone V. (2006) Role of acetaldehyde in mediating the pharmacological and behavioral effects of alcohol. Alcohol Res Health 29:258-265. Rivera-Meza M, Quintanilla ME, Tampier L, Mura CV, Sapag A, Israel Y. (2010) Mechanism of protection against alcoholism by an alcohol dehydrogenase polymorphism: Development of an animal model. FASEB J 24:266-274. Wall TL, Carr LG, Ehlers CL. (2003) Protective association of genetic variation in alcohol dehydrogenase with alcohol dependence in native american mission indians. Am J Psychiatry 160:41-46. Zakhari S. (2006) Overview: How is alcohol metabolized by the body? Alcohol Res Health 29:245-254.