Association of Polymorphisms in DME and Drug Transporters with Disease Susceptibility and Progression

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The association of DME polymorphisms with disease susceptibility has mainly been explored in models of environmental carcinogenesis (7). In theory, genetic polymorphisms could

Table 1 Application of Pharmacogenetics in Clinical Gastroenterology and Hepatology

Disease susceptibility and phenotype

DME polymorphism in alcoholic liver disease mEH polymorphism in HCV-related liver disease mEH and GSTM1 polymorphism in hepatocellular carcinoma MDR1 gene polymorphism in inflammatory bowel disease Efficacy of therapy

Drug metabolism and disposal

TPMT genotype in treatment of IBD with azathioprine CYP2C19 genotype and efficacy of proton pump inhibitors Drug targets

SERT polymorphism and treatment of IBS with alosetron Mutations in the ISDR and treatment of HCV-1B infection Adverse drug reaction

Adverse gastrointestinal reactions

Irinotecan toxicity Adverse hepatic reactions

Gilbert's syndrome and Indinavir-induced hyperbilirubinemia NAT2 polymorphism and isoniazid-induced hepatotoxicity HLA association of co-amoxiclav-induced jaundice

Abbreviations: DME, drug-metabolizing enzymes; HCV, hepatitis C virus; TPMT, thiopurine methyl transferase; HLA, human leukocyte antigen; IBD, inflammatory bowel disease; IBS, irritable bowel syndrome; SERT, serotonin transporter gene; ISDR, interferon sensitivity-determining region.

account for heterogeneity in disease progression and also in the predisposition to complications. They may therefore assist in identifying phenotypic subgroups of common diseases.

Alcoholic Liver Disease

Deaths from chronic liver disease have increased threefold in the United Kingdom during the last three decades (8). The mortality can largely be attributed to alcoholic liver disease and viral hepatitis. Two-thirds of deaths from liver cirrhosis occur in patients under the age of 65 years (8). Alcohol is a major contributor to death, injuries, and illness, accounting for 10.3% of disability adjusted life years among established market economies, compared with 11.7% for tobacco and 2.3% for illicit drugs. The U.S. Veterans Administration Twin Panel Study showed a higher concordance for cirrhosis in monozygotic twins (17%) compared with dizygotic twins (5%), indicating that genetic factors contribute to susceptibility although most of the liability for cirrhosis occurs due to the shared risk for alcoholism (9,10). The strongest genetic association with alcoholism has been shown to be with genes encoding alcohol-metabolizing enzymes.

Ethanol is rapidly absorbed from the gastrointestinal tract with most being metabolized in the liver. Hepatic oxidation of ethanol to acetaldehyde is carried out by the alcohol dehydrogenase (ADH) in the cytosol, with variable contribution by cytochrome P450 2E1 (CYP2E1) in microsomes and catalase in peroxisomes (Fig. 1). Aldehyde dehy-drogenases (ALDH), especially the mitochondrial form ALDH2, convert acetaldehyde to acetate. The resultant production of acetaldehyde and reactive oxygen species may lead to liver injury either by inducing lipid peroxidation or by formation of protein adducts, which in turn leads to liver injury through an immune-mediated mechanism (11). Polymorphisms in the alcohol and aldehyde dehydrogenase genes result in considerable interindividual variation in the rate at which both ethanol and acetaldehyde are metabolized.

Biliverdin Ixa

Figure 1 Pathways of alcohol metabolism. Abbreviations: ADH, alcohol dehydrogenase; NAD, nicotinamide-adenine dinucleotide; NADH, nicotinamide-adenine dinucleotide, reduced; NADPH, nicotinamide-adenine dinucleotide phosphate, reduced; NADP, nicotinamide-adenine dinucleotide phosphate; ALDH, aldehyde dehydrogenase.

Figure 1 Pathways of alcohol metabolism. Abbreviations: ADH, alcohol dehydrogenase; NAD, nicotinamide-adenine dinucleotide; NADH, nicotinamide-adenine dinucleotide, reduced; NADPH, nicotinamide-adenine dinucleotide phosphate, reduced; NADP, nicotinamide-adenine dinucleotide phosphate; ALDH, aldehyde dehydrogenase.

Humans have two polymorphic ADH gene loci, ADH2 and ADH3 (12). Alleles with high enzyme activity (ADH2*2 and ADH3*1) appear to be less frequent in alcohol-dependent subjects as these are associated with a high acetaldehyde concentration, which has an aversive effect. Possession of the ADH2*2 allele has been associated with increased susceptibility to alcoholic liver disease in the Japanese (13). However, the evidence for such an association in Caucasians has been inconsistent, with two small studies suggesting an association of ADH3 *1 with advanced liver disease (14,15), whereas three other studies found no difference in ADH genotype frequencies between cases and controls (16-18). A polymorphism in ALDH2 is common in Asians, and individuals homozygous for the variant allele (ALDH2*2) lack mitochondrial ALDH2 enzyme activity. Accumulation of acetaldehyde in these subjects leads to facial flushing, tachycardia, nausea, and vomiting even with moderate alcohol consumption. As the point mutation acts as a dominant negative, those heterozygous for the variant ALDH2 allele have a marked reduction in the activity of ALDH2. Asians with the ALDH2 *2 allele have an increased susceptibility to advanced liver disease, presumably through the accumulation of acetaldehyde (19). There is currently no evidence for the existence of similar polymorphisms in the ALDH2 gene in Caucasians.

CYP2E1 is associated with NADPH-CYP450 reductase in the microsomal membrane and oxidizes ethanol to acetaldehyde (20). CYP2E1 has a high Km for ethanol but is inducible by chronic drinking. Metabolism of ethanol by CYP2E1 generates reactive oxygen species including the hydroxyl radical (OH"), superoxide anion (O"), and hydrogen peroxide (H2O2), and hence could induce lipid peroxidation. Several restriction fragment length polymorphisms (RFLPs) in the upstream and noncoding regions of CYP2E1 have been identified. Although individual studies have found an association of the variant CYP2E1*5 allele with advanced liver disease among Caucasians (17,21), a meta-analysis of published studies did not confirm the association with alcoholic liver disease (22).

Viral Hepatitis

An estimated 0.5% to 1% of the U.K. population and 170 million people worldwide are infected with the hepatitis C virus (HCV). Chronic hepatitis related to HCV is the most common cause of cirrhosis and hepatocellular carcinoma in Europe and the United States. Overall, about 20% of the infected individuals develop cirrhosis or hepatocellular carcinoma over a 20- to 30-year period (23). Several environmental, host, and viral factors are likely to interact in determining individual susceptibility to progressive disease. Risk factors, such as male gender, age at infection, mode of transmission, alcohol consumption, and hepatitis B virus coinfection, are associated with more rapid disease progression, although these account for only a small part of the variability in the disease.

Epoxide hydrolase catalyzes the irreversible hydration of highly reactive alkene epoxides and arene oxides generated by CYP450-dependent oxidation to yield metabolites that can be readily conjugated and excreted (24). In the liver, the distribution of epoxide hydrolase parallels that of CYP450 being located in the centrilobular region (zone 3). The enzyme plays an important role in detoxifying electrophilic epoxides that might otherwise bind to proteins and nucleic acids and cause cellular toxicity and genetic mutation. Micro-somal epoxide hydroxylase (mEH) is involved in the metabolism of a wide variety of xenobiotics and has been found in virtually all tissues, including liver, kidney, lung, and testis (25). Two point mutations in exons 3 and 4 lead to the amino acid changes, Tyr113His and His139Arg, respectively, which affect mEH activity by influencing protein stability (26,27). In a study involving 394 patients at different stages of HCV-related liver disease, patients homozygous for the exon 3 variant allele (113 His/His) were overrepresented in advanced stages of the disease (28), being associated with a threefold increased risk of cirrhosis and a fivefold increased risk of hepatocellular carcinoma. The association was stronger in men. When the exon 3 and exon 4 genotypes were combined to express the metabolic phenotype, very slow metabolizers were highly prevalent among patients with cirrhosis and hepatocellular carcinoma (28). The independent role of mEH polymorphisms in cancer risk suggests that the reduced disposal of specific classes of compounds, such as aflatoxin B1, may be important in the pathogenesis.

Aflatoxin B1 is considered to be a hepatocarcinogen in humans. It has been postulated that aflatoxin B1 induces carcinogenesis by causing a mutation in the tumor suppressor gene p53 at codon 249 (29,30). An individual's capacity to detoxify the mutagenic metabolite aflatoxin 8,9-epoxide by mEH and glutathione-S-transferase (GST) M1 could determine the amount of epoxide available to bind to DNA. In two populations in Ghana and China, a significant association was found between the mEH exon 3 variant allele and presence of the aflatoxin B1-albumin adduct (indicative of exposure to aflatoxin B1) and hepatocellular carcinoma (31). In addition, a synergistic relationship between the mEH variant allele and hepatitis B surface antigen was demonstrated. Thus, individuals with only the mEH variant allele had a threefold increased risk, those with hepatitis B infection had a 15-fold increased risk, whereas subjects with both the hepatitis B surface antigen and the mEH variant allele had a 77-fold risk of hepatocellular carcinoma, whereas compared with individuals without either of the risk factor. The frequency of the GSTM1 null genotype, which abolishes GSTM1 enzyme activity (32), was also greater in patients with hepatocellular carcinoma, although the association was not as strong. The p53 codon 249 mutation was observed only among hepatocellular carcinoma patients with one or more of the high-risk genotype for either mEH or GSTM1 (31).

Inflammatory Bowel Disease

Crohn's disease and ulcerative colitis are common causes of gastrointestinal morbidity in Western countries, with a combined prevalence of 100 to 200 cases per 100,000 population (33).

Microbial, immunologic, and genetic factors are thought to be involved in the pathogenesis of inflammatory bowel disease. An experimental model of UC in mice deficient for the multidrug resistant 1 (mdr 1a) gene product P-glycoprotein (Pgp) showed that adenosine triphosphate (ATP)-binding cassette transporters probably have an important barrier function in protecting against xenobiotics, bacteria, and their toxins (34,35). In humans, Pgp (ABCB1) is localized to the apical membrane of epithelial cells in both the small and large intestines (36). The exon 26 C3435T polymorphism in the MDR1 gene affects Pgp expression in the intestine, with individuals homozygous for the T allele having the lowest expression (37). Presumably, impairment of barrier function in these subjects makes them more susceptible to the development of ulcerative colitis (38). In contrast, high Pgp expression may be associated with poor response to medical therapy in patients with inflammatory bowel disease (39). In addition, the MDR1 C3435T polymorphism may also play an important role in determining the disease phenotype. In a case-control study, subjects with the CC genotype had a higher prevalence of penetrating or stricturing Crohn's disease (38). The 3435CC genotype was also found to have a higher prevalence in patients with Crohn's disease requiring azathioprine or 6-mercaptopurine (38).

Association of Genetic Polymorphisms with Drug Efficacy

A patient's response to a drug depends on many factors, including absorption and distribution of the drug, drug metabolism and elimination, concentration of the drug at the target site, and the number and function of the target receptors. It is possible to identify genetic polymorphisms in all of these processes, which could theoretically influence the drug response phenotype in individual patients, and allow identification of those patients with a greater chance of responding to the particular medication.

Genetic Polymorphisms in Drug Metabolism and Disposal

Studies investigating associations between specific drug metabolizing enzyme genotypes with drug response have sometimes reached different and, at times, apparently conflicting conclusions. There may be many reasons for this, including differences in ethnic populations studied, heterogeneous disease phenotypes, differences in the endpoints used to define response, and the polygenic nature of many drug effects.

Azathioprine in Inflammatory Bowel Disease. Immunomodulatory therapy with azathioprine and 6-mercaptopurine has been shown to be effective in both steroid-dependent and resistant cases of inflammatory bowel disease, achieving and maintaining remission in 70% of the patients (40). However, a delay of 7 to 14 weeks before the onset of therapeutic benefit and concern regarding toxicity have limited their use in inflammatory bowel disease. Azathioprine is a prodrug, which is converted to 6-mercaptopurine by non-enzymatic cleavage (Fig. 2) (41). 6-mercaptopurine is rapidly taken up by erythro-cytes and other tissues. Intracellular biotransformation of 6-mercaptopurine occurs via two competing routes. The drug is catabolized into the inactive 6-methylmercaptopurine by thiopurine methyl transferase (TPMT) or anabolized to the active thioguanine nucleo-tides by hypoxanthine phosphoribosyltransferase. Incorporation of 6-thioguanine nucleotides into lymphocyte DNA induces cytotoxicity and immunosuppression.

Interindividual and interethnic variability in TPMT activity is caused by polymorphisms in the gene (42). Measurement of TPMT activity in erythrocytes has shown that about 1 in 300 of various European populations have undetectable activity (homozygous for variant alleles TPMTL), 11% inherit intermediate levels (heterozygous TPMTH/ TPMTL), whereas 89% have high enzyme activity (homozygous for wild-type TPMTL) (43). The molecular basis of the variation in enzyme activity has been studied. Although a number of variant TPMT alleles have been described, the most common polymorphisms

Azathioprine

Methyl-mtro-

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