**Pharmacogenetics – A Treatment Strategy for Alcoholism**

Anjana Munshi\* and Vandana Sharma *Institute Of Genetics and Hospital for Genetic Diseases, Osmania University, Begumpet, Hyderabad, India* 

#### **1. Introduction**

230 Pharmacology

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Alcoholism is a complex relapsing disorder of heterogeneous etiology, affecting people internationally. Alcohol dependence is a cumulative response of inability to stop drinking, craving and developing the symptoms of physical dependence and tolerance. In past two decades, mounting evidence has suggested that alcoholism or alcohol addiction is a host of major psychological, social, financial and health problems (Poznyak et al., 2005). According to World Health Organization, alcoholism is responsible for 4% of global disease burden and is the third major preventable risk factor for premature death and disability in developed nations (World Health Organization, 2002). Although, the exclusive biological mechanisms underlying the development of alcoholism are still uncertain, the major risk factors contributing towards the development of alcoholism are age (adolescents are at higher risk of developing alcoholism), gender (men are more prone to develop alcoholism as compared to women due to depression), personality (experience seeking), and psychiatric or behavioral disorders. The prevalence, age of onset, clinical symptoms and outcome of alcoholism differs from individual to individual and varies according to ethnicity (Kenneth et al., 2011). In addition to this, lower social status and low education have also been found to be associated with alcoholism in cross sectional and longitudinal studies (Fukuda et al., 2005; Poznyak et al., 2005; Subramanian et al., 2005; Wray et al., 2005).

According to World Health Organization report on global alcohol status, it has been found that approximately 2 billion people consume alcoholic beverages and there are about 76.3 million people with diagnosable alcohol disorder (World Health Organization, 2004). In India the prevalence of alcoholism has been found to be 21.4% as recoded by epidemiological surveys (Benegal, 2005).The deleterious effects of alcohol on central nervous system can be observed in the form of changes in mood and personality, anxiety and depression. Although, it affects all the organs in the body, brain neurotransmitters are the main target sites of alcohol (Wertheimer et al., 2003). The specific physiological effects of alcohol depend on dose, concentration in blood, absorption, distribution, metabolism, excretory conditions, prior drinking experience, concurrent use of other drugs, and

<sup>\*</sup> Corresponding Author

Pharmacogenetics – A Treatment Strategy for Alcoholism 233

treatments. This will improve the treatment of alcoholism. Alcohol pharmacogenetics has great potential in improving treatment strategies for alcoholism (Radel and Goldman, 2001; Quickfall and el-Guebaly, 2006). The treatment strategy of combining clinician's views based on genotypic information would individualize and optimize the treatment for alcoholism with best possible outcome of individual's good health free of alcohol dependence. Pharmacogenetics is expected to add new dimensions and would tailor the therapeutic

The chapter provides an overview of the molecular, pharmacological and neurological aspects of alcoholism with main emphasis on pharmacogenetics of alcoholism treatment.

Alcohol is generally taken orally, absorbed unchanged through the whole length of digestive tract. Almost 20% absorption takes place rapidly through stomach and 80% through small gut (Caballeria, 2003). The rate of absorption depends on volume, concentration, nature of alcoholic drink, presence and absence of food in stomach, permeability of gastric and intestinal tissues and genetic variation. After absorption into the blood-stream, alcohol is distributed quickly throughout the total body fluid (Pawan, 1972). The distribution of alcohol is accelerated by vascularization and blood flow e.g. organs rich in blood supply such as brain and lungs achieve the higher initial concentrations of alcohol. Liver is the main site of alcohol metabolism. In hepatocytes three systems are involved in alcohol metabolism located in three different cellular compartments. These are alcohol dehydrogenase (*ADH*) located in cytosol, microsomal ethanol oxidizing system (*MEOS*) situated in endoplasmic reticulum and catalase in peroxisomes (Caballeria, 2003). These are

The metabolic pathway involves conversion of alcohol (ethanol) to acetaldehyde via oxidation catalyzed by *ADH* in cytoplasm of hepatocytes, a rate limiting step. The second reaction is catalyzed by aldehyde dehydrogenases (*ALDH*), acetaldehyde is converted to acetic acid and finally to carbon dioxide and water through citric acid cycle into circulation. Acetaldehyde plays central role in the toxicity produced by alcohol consumption as in liver it reaches to saturation point and escapes into blood circulation. Further it impairs mitochondrial functions and reactions leading to damage of hepatocytes. The rate of metabolism of alcohol differs from person to person because it is influenced by genetic

Alcohol dehydrogenase (ADH) occurs in multiple forms and is encoded by 7 different genes. These are ADH1A, ADH1B, ADH1C, ADH4, ADH5, ADH6 and ADH7. These genes are aligned along a small region of chromosome 4. ADH enzymes encoded by ADH gene function as dimers i.e. the active forms are composed of two subunits. On the basis of their similar amino acid sequences and kinetic properties, these seven ADH types have been divided into five classes. The class I genes ADH1A, ADH1B and ADH1C are closely related. These encode for α, β and γ subunits respectively, which form homodimers or heterodimers and account for most of the alcohol oxidizing capacity in liver (Hurley et al., 2002; Lee et al.,

involved in conversion of alcohol to acetaldehyde (Figure 1).

**2.1 Alcohol dehydrogenase system** 

variants of metabolizing enzymes mentioned above (Quertemont, 2004).

treatment of alcoholism.

**2. Metabolism of alcohol** 

comorbid conditions. The body adapts metabolically and neurally to repeated exposure of alcohol so as to develop tolerance (Zaleski et al., 2004).

Recent advances in the field of neurobiology have improved our understanding about associated risk factors and neurochemical mechanisms responsible for the development of alcoholism. Evidences suggest that there is large inter-individual variation in terms of development of alcohol dependence and treatment of alcoholism. People consume alcohol and respond to its effects in a number of ways e.g. some develop no side effects even in moderate to higher levels and some may develop problems even when consumed in smaller doses. This variation is the result of individual's genetic makeup directly influencing the metabolism of alcohol (Strat et al., 2008).

Genetic factors have been found to play a critical role in the etiology of alcoholism (Heath et al., 2001; Sloan et al., 2008; Kenneth et al., 2011). Researchers have suggested that 50-60% of alcohol dependence is determined by genetics (Goldman and Bergen 1998; McGue et al., 1999). Based on results of adoption, twin, and family studies it is now clear that the vulnerability to alcoholism is determined by genetic factors as well as by environmental factors (Moussas et al., 2009). However, it is difficult to determine the individual determinant of alcoholism (Flensborg-Madsen et al., 2007). The candidate gene approach has revealed a number of biomarkers, which are responsible for alcoholism. Certain variants of alcohol dehydrogenase and aldehyde dehydrogenase genes (genes encoding for alcohol metabolizing enzymes) have been found to alter the metabolism of alcohol in a dramatic way (Nurnberger et al., 2004). In addition to this, polymorphisms in neurotransmitter genes (target receptor genes) such as gamma amino butyric acid and opioid receptor genes have also been reported to be associated with marked risk of alcohol dependence (Strat et al., 2008). Current treatment approaches to alcoholism are moderately effective with perhaps as many as half of the patients receiving treatment due to abstinent or significantly reducing episodes of binge drinking (Group, 1997). Pharmacotherapy and behavioral therapy including psychosocial support are two main types of treatment in alcoholism. The pharmacological agents approved by FDA prescribed in the treatment of alcoholism are disulfiran (antabuse), naltrexone (revia), acamprosate (campral) and Vivitrol (Krishnan-Sarin & O'Malley et al., 2008).

The major drawback of ineffectiveness of pharmacotherapy of alcoholism is inter-individual variation in response to medication (Radel and Goldman, 2001). There are individuals, showing lesser/no therapeutic efficacy of a drug prescribed, known as non-responders. Another group of individuals showing high therapeutic efficacy towards the same drug are known as responders (McLeod et al., 2000).

Recent advances in the area of molecular biology have increased our knowledge of understanding the influence of genetic variants on pharmacokinetic and pharmacodynamic profile of alcohol and neurobiology of alcoholism (Ray et al., 2010a). The unavoidable alcohol withdrawl symptoms, depression, unpredicted death, medical complications, socioeconomic repercussions of alcoholism suggest that the treatment strategies should be improved with new and targeted approach of pharmacogenetics.

Pharmacogenetics is a measure of predicting individual's genetic profile responsible for variable drug responses. The genetic analysis along with consideration of other factors of alcoholic patients can lead to the identification of clinical subtypes of patients with specific treatments. This will improve the treatment of alcoholism. Alcohol pharmacogenetics has great potential in improving treatment strategies for alcoholism (Radel and Goldman, 2001; Quickfall and el-Guebaly, 2006). The treatment strategy of combining clinician's views based on genotypic information would individualize and optimize the treatment for alcoholism with best possible outcome of individual's good health free of alcohol dependence. Pharmacogenetics is expected to add new dimensions and would tailor the therapeutic treatment of alcoholism.

The chapter provides an overview of the molecular, pharmacological and neurological aspects of alcoholism with main emphasis on pharmacogenetics of alcoholism treatment.
