**10. Cytochrome P450**

*The Recent Topics in Genetic Polymorphisms*

by *ADH1B\*3* gene [43].

acetaldehyde [44, 45].

with *ADH1B\*1* [49]*.*

**9.1 ADH**

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

consumption habits and risk of alcoholism development.

without a family history of the esophageal cancer [52, 53].

dinucleotide (NAD) is reduced to NADH providing reduced cytosolic environment in the liver cells. Because of byproduct like highly reactive and toxic free radicals and acetaldehyde, the liver cells become more vulnerable to damage [17]. Control of ADH activity is complex and involves: (a) dissociation of the product NADH which is a rate limiting step and (b) product inhibition by NADH and acetaldehyde [14]. ADH comprises of a complex family. In humans on the basis of kinetic and structural properties, enzyme ADH has been categorized into five classes. Most of them are found in liver, stomach and lungs except ADH5 found in most tissues [17]. If alcohol concentration is high, it is eliminated at a higher rate because of high activity of enzymes viz. class II ADH encoded by *ADH4* gene and β3-ADH encoded

Aldehyde dehydrogenase (ALDH2) rapidly metabolizes acetaldehyde (produced by alcohol oxidation) to acetate and NADH. NADH is then oxidized through electron transport chain, or respiratory chain enzymes [17]. Among various isozymes of ALDH, only the cytosolic ALDH1 and the mitochondrial ALDH2 can metabolize

Genetic polymorphism in *ADH1B* and *ADH1C* gene locations is associated with

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

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

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

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

**128**

**9.2 ALDH**

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 with other substances to create carcinogenic compounds [55].
