**9. Genetic Polymorphism in ADH and ALDH2**

#### **9.1 ADH**

Genetic polymorphism in *ADH1B* and *ADH1C* gene locations is associated with different levels of enzyme activity [46]. In different population *ADH1B* occur at different frequencies. For example, in Caucasian and black populations it is predominant, whereas in Chinese, Japanese and in some people of Jewish ancestry *ADH1B\*2* frequency is higher. In case of Caucasian populations, *ADH1C\*1* and *ADH1C\*2* appear with equal frequency [47]. People of Jewish descent carrying the *ADH1B\*2* allele show only marginally (<15%) higher alcohol elimination rates compared to people with *ADH1B\*1*. Also, African Americans [48] and native Americans with the *ADH1B\*3* allele metabolize alcohol at a faster rate than those with *ADH1B\*1* [49]*.*

Variants in both ADH and ALDH2 genes can influence alcohol metabolism by either increasing turnover of ethanol to acetaldehyde or deactivating oxidization function of acetaldehyde to harmless acetic acid [34, 50]. This can result in accumulation of acetaldehyde, which is a known mutagen and carcinogen that cause DNA damage and promote esophageal squamous cell carcinoma (ESCC) development [51]. In addition, ADH and ALDH2 alleles may influence individual alcohol consumption habits and risk of alcoholism development.

Information on alcohol consumption, sex, and family history is essential in risk analyses of alcohol-related variants for several reasons. First, alcohol consumption could be a strong confounding variable and effect modifier in comparing genotypes and the risk of ESCC because genotypes and alcohol consumption are interrelated. Second, alcohol-related enzymes do not play a major role in ESCC development among alcohol nondrinkers, or females who drink lesser alcohol than males. Also the adverse role of loss-of-functional *ADH* and ALDH variants will increase in alcohol drinkers. Third, the mechanism of tumorigenesis may not be same with and without a family history of the esophageal cancer [52, 53].

#### **9.2 ALDH**

The allelic variants *ALDH2\*1* and *ALDH2\*2* resulted from genetic polymorphism of *ALDH2* gene is inactive showing no acetaldehyde metabolism *in vitro*.

**129**

**12. Catalase**

*Genetic Polymorphism and Alcohol Metabolism DOI: http://dx.doi.org/10.5772/intechopen.88907*

negative physiological responses to alcohol.

**10. Cytochrome P450**

After alcohol consumption level of acetaldehyde is high in people having heterozygous or homozygous condition for *ALDH2\*2* allele [44, 45] and therefore experience

Cytochrome P450 enzymes are present in almost all tissues of the body and play important roles in hormone synthesis and breakdown including estrogen and testosterone, cholesterol synthesis and vitamin D metabolism. Cytochrome P450 enzymes also function to metabolize potentially toxic compounds, for example, drugs and bilirubin, principally in the liver [54]. The cytochrome P450 isozymes, including CYP2E1, 1A2, and 3A4 which are present predominantly in the microsomes or endoplasmic reticulum, also contribute to alcohol oxidation in the liver. However, CYP2E1 is active only after a person consume large amount of alcohol, and catalase metabolizes only a small fraction of alcohol in the body [47]. This enzyme is induced when alcohol concentration is high and it metabolizes alcohol in to acetaldehyde. It also oxidizes alcohol in tissue like brain where ADH activity is low. It produces ROS which increase the risk of tissue damage [17]. When alcohol is metabolized by CYP2E1, highly reactive oxygen containing molecules or reactive oxygen species (ROS) is produced. ROS can damage proteins and DNA or interact

CYP2E1 enzyme is an important member of the cytochrome P450 family. It is a naturally ethanol-inducible enzyme involved in alcohol metabolism. Polymorphism in *Rsa*I/*Pst*I in the promoter gene region increases transcriptional activity of the gene which may play an important role in the development of esophageal carcinoma [56]. *CYP2E1 c1/c1* genotype found at increased risk for gastric cardia cancer (GCC).

Catalase (in peroxisomes) is capable of oxidizing ethanol *in vitro* in the presence

of a hydrogen peroxide (H2O2) generating system, such as the enzyme complex

Individuals with this genotype and have a history of heavy cigarette smoking were at increased risk for GCC. This suggests that the interaction of the *CYP2E1* polymorphism with smoking has a great influence on susceptibility to GCC [57]. Polymorphisms in *CYP2E1* involved in the metabolism of carcinogens tobacco and alcohol, leads to Head and Neck Squamous Cell Carcinoma (HNSCC). Haplotype analysis revealed that haplotype T-A was associated with a greater than 10-fold increase in risk for HNSCC. Use of alcohol or tobacco interact with *CYP2E1* variant genotypes or with *GSTM1* or *XRCC1 and increases the* risk of HNSCC suggest the importance of gene–gene and gene–environment interactions in the development of HNSCC [58]. There was no risk of ESCC found associated with CYP2A6, CYP2E1, GSTM1 polymorphism suggest an opposite role of GSTP1 and GSTT1 polymorphisms for ESCC [59]. Gene polymorphism in GSTM1, GSTT1, GSTP1, CYP1A1 and CYP2E1 represent risk-modifying factors for ethanol related diseases in Brazilian alcoholics and controls with similar ethnic backgrounds. Also the persons with these genotypes are genetically more prone to the development of alcoholic pancreatitis and

with other substances to create carcinogenic compounds [55].

**11. Genetic polymorphism in CYP2E1**

alcoholic cirrhosis, respectively [60–63].

After alcohol consumption level of acetaldehyde is high in people having heterozygous or homozygous condition for *ALDH2\*2* allele [44, 45] and therefore experience negative physiological responses to alcohol.
