**3. Genetics behind ethanol metabolism**

Important factors that can influence responses to alcohol are variations in alcohol-metabolizing enzymes. Genetically influenced metabolic factors have been implicated in the etiology of alcoholism among different ethnic groups. Several genetically determined variants of ADH and ALDH enzymes exist that differ in their level of activity and different people have different variants of these enzymes. Some of these enzyme variants work more or less efficiently than others; this means that some people can break down ethanol to acetaldehyde, or acetaldehyde to acetate, more quickly than others. The type of ADH and ALDH an individual carries has been shown to influence how much he or she drinks, which in turn influences his or her risk for developing alcoholism [8].

Genetic differences in ADH and ALDH enzymes may help to explain why some ethnic groups have higher or lower rates of alcohol-related problems. There are multiple ADH and ALDH enzymes that are encoded by different genes. These genes occur in several variants and the enzymes encoded by these alleles can differ in the rate at which they metabolize ethanol or acetaldehyde or in the levels at which they are produced and these variants have been shown to influence a person's drinking levels and consequently the risk of developing alcohol abuse or dependence [8]. Studies have shown that people carrying certain ADH and ALDH alleles are at significantly reduced risk of becoming alcohol dependent. The mechanism through which ADH and ALDH variants influence alcoholism risk is thorough the elevation of acetaldehyde levels, resulting either from a more rapid ethanol oxidation or from slower acetaldehyde oxidation. Acetaldehyde is a toxic substance whose accumulation leads to a highly aversive reaction.

Humans have seven different ADH genes called ADH1A, ADH1B, ADH1C, ADH4, ADH5, ADH6, and ADH7 and there are three different ADH1B alleles: the ADH1B\*1 allele, ADH1B\*2 (this allele is common in Asians) and the ADH1B\*3 (this allele primarily is found in people of African descent) alleles. The ADH1B\*2 allele is associated with rapid ethanol oxidation and has shown protective effects against alcohol dependence in a variety of populations and ethnic groups. ADH1B\*2 allele is found at high frequency in East Asians and it has been shown to be protective against alcoholism [8, 9]. ADH1B\*2 allele is not very common in European or

**39**

*Ethanol*

*DOI: http://dx.doi.org/10.5772/intechopen.79861*

the highly aversive reactions.

alcohol dehydrogenase (ADH) (**Figure 4**).

African populations but also provides protection against alcoholism [10]. ADH1B\*2 allele is found at moderate frequencies among people of Jewish descent and reduces binge drinking and risk for alcoholism [11, 12]. The protective effect of ADH1B\*2 appears to be weaker in European than in Asian populations [10]. This difference could result from different social and environmental factors. The ADH1B\*3 allele had a significant protective effect on risk for alcoholism in a set of African-

Numerous polymorphisms exist in the human ALDH genes, some of which cause inborn errors of metabolism and contribute to clinically relevant diseases [14]. Several isozymes of ALDH have been identified, but only the cytosolic ALDH1 and the mitochondrial ALDH2 metabolize acetaldehyde produced during ethanol oxidation [8, 15]. Polymorphism in the ALDH2 gene is associated with altered acetaldehyde metabolism, alcohol-induced 'flushing' syndrome, decreased risk for alcoholism and increased risk of ethanol-induced cancers. Genetic polymorphism of the ALDH2 gene result in allelic variants ALDH2\*1 and ALDH2\*2. ALDH2\*2 allele is relatively common in people of Chinese, Japanese, and Korean descent but is essentially absent in people of European or African descent [8, 16]. People carrying an ALDH2\*2 allele show an alcohol flush reaction, even when they consume only relatively small amounts of alcohol [17]. In these people, acetaldehyde levels in the blood increase from nearly undetectable levels to levels high enough to trigger

American families selected for having multiple alcoholic members [13].

**4. Metabolic pathways and hosts for ethanol production**

Ethanol is produced from glucose via fermentative consumption of pyruvate, the end product of glycolysis [18]. Glycolysis is a metabolic process that converts glucose to pyruvate while producing ATP. The pyruvate formed by glycolysis is further metabolized via one of the three catabolic routes. In aerobic organisms or tissues, under aerobic conditions, pyruvate is oxidized with the loss of its carboxyl group as CO2 to yield the acetyl-CoA; the acetyl-CoA is then completely oxidized to CO2 in the citric acid cycle (**Figure 4**). The second route for pyruvate is its reduction to lactate via lactic acid fermentation in vigorously contracting muscle. Under anaerobic condition, pyruvate is reduced to lactate. Another major route of pyruvate catabolism leads to ethanol. In some plant tissues and certain invertebrates, protists and microorganisms such as brewer's yeast, pyruvate under anaerobic conditions can be fermented to ethanol by sequential reactions of pyruvate decarboxylase (PDC) and

Microbial fermentation was introduced by Louis Pasteur in the late 1850s and was the first to recognize the relationship between the presence of yeast cells and the conversion of sugar to ethanol. Today ethanol producing *Saccharomyces cerevisiae* (yeast) have been exploited to produce a wide variety of alcoholic beverages and biofuels. Many microorganisms are being used for ethanol and biofuel production, but all have certain limitations such as industrial robustness, substrate utilization, productivity and yield. *Saccharomyces cerevisiae* (yeast) is a leading traditional industrial biocatalyst microorganism for ethanol production and with technological advancement in genetic engineering, bacteria such as *Escherichia coli*, *Zymomonas mobilis*, *Corynebacterium glutamicum* and *Bacillus subtilis* have been developed [19]. *Zymomonas mobilis* (*Z. mobilis*), a bacterium commonly found in plant saps and in honey has many desirable industrial biocatalyst characteristics and has been suggested as an alternative to the classical model, *Saccharomyces cerevisiae* (yeast) due to its advantage for ethanol yield. *Saccharomyces cerevisiae* uses the Embden-Meyerhof-Parnas (EMP) pathway for glycolysis while *Z. mobilis* uses the Entner-Doudoroff

#### *Ethanol DOI: http://dx.doi.org/10.5772/intechopen.79861*

*Psychology of Health - Biopsychosocial Approach*

**3. Genetics behind ethanol metabolism**

**Figure 3.**

ences his or her risk for developing alcoholism [8].

tion leads to a highly aversive reaction.

Important factors that can influence responses to alcohol are variations in alcohol-metabolizing enzymes. Genetically influenced metabolic factors have been implicated in the etiology of alcoholism among different ethnic groups. Several genetically determined variants of ADH and ALDH enzymes exist that differ in their level of activity and different people have different variants of these enzymes. Some of these enzyme variants work more or less efficiently than others; this means that some people can break down ethanol to acetaldehyde, or acetaldehyde to acetate, more quickly than others. The type of ADH and ALDH an individual carries has been shown to influence how much he or she drinks, which in turn influ-

*mitochondrial pyruvate carrier; 2: pyruvate dehydrogenase complex; 3: pyruvate decarboxylase; 4: acetaldehyde dehydrogenase; 5: acetyl-CoA synthetase; 6: carnitine shuttle; 7: alcohol dehydrogenase; 8: pyruvate carboxylase.*

*Metabolism of ethanol to acetyl CoA. Numbered reactions are catalyzed by the following enzymes: 1:* 

Genetic differences in ADH and ALDH enzymes may help to explain why some ethnic groups have higher or lower rates of alcohol-related problems. There are multiple ADH and ALDH enzymes that are encoded by different genes. These genes occur in several variants and the enzymes encoded by these alleles can differ in the rate at which they metabolize ethanol or acetaldehyde or in the levels at which they are produced and these variants have been shown to influence a person's drinking levels and consequently the risk of developing alcohol abuse or dependence [8]. Studies have shown that people carrying certain ADH and ALDH alleles are at significantly reduced risk of becoming alcohol dependent. The mechanism through which ADH and ALDH variants influence alcoholism risk is thorough the elevation of acetaldehyde levels, resulting either from a more rapid ethanol oxidation or from slower acetaldehyde oxidation. Acetaldehyde is a toxic substance whose accumula-

Humans have seven different ADH genes called ADH1A, ADH1B, ADH1C, ADH4, ADH5, ADH6, and ADH7 and there are three different ADH1B alleles: the ADH1B\*1 allele, ADH1B\*2 (this allele is common in Asians) and the ADH1B\*3 (this allele primarily is found in people of African descent) alleles. The ADH1B\*2 allele is associated with rapid ethanol oxidation and has shown protective effects against alcohol dependence in a variety of populations and ethnic groups. ADH1B\*2 allele is found at high frequency in East Asians and it has been shown to be protective against alcoholism [8, 9]. ADH1B\*2 allele is not very common in European or

**38**

African populations but also provides protection against alcoholism [10]. ADH1B\*2 allele is found at moderate frequencies among people of Jewish descent and reduces binge drinking and risk for alcoholism [11, 12]. The protective effect of ADH1B\*2 appears to be weaker in European than in Asian populations [10]. This difference could result from different social and environmental factors. The ADH1B\*3 allele had a significant protective effect on risk for alcoholism in a set of African-American families selected for having multiple alcoholic members [13].

Numerous polymorphisms exist in the human ALDH genes, some of which cause inborn errors of metabolism and contribute to clinically relevant diseases [14]. Several isozymes of ALDH have been identified, but only the cytosolic ALDH1 and the mitochondrial ALDH2 metabolize acetaldehyde produced during ethanol oxidation [8, 15]. Polymorphism in the ALDH2 gene is associated with altered acetaldehyde metabolism, alcohol-induced 'flushing' syndrome, decreased risk for alcoholism and increased risk of ethanol-induced cancers. Genetic polymorphism of the ALDH2 gene result in allelic variants ALDH2\*1 and ALDH2\*2. ALDH2\*2 allele is relatively common in people of Chinese, Japanese, and Korean descent but is essentially absent in people of European or African descent [8, 16]. People carrying an ALDH2\*2 allele show an alcohol flush reaction, even when they consume only relatively small amounts of alcohol [17]. In these people, acetaldehyde levels in the blood increase from nearly undetectable levels to levels high enough to trigger the highly aversive reactions.
