The current 'fixed-dosage strategy' approach to medicine, means there is much inter-individual variation in drug response. Pharmacogenetics is the study of how inter-individual variations in the DNA sequence of specific genes affect drug responses. This article will highlight current pharmacogenetic knowledge on important drug metabolizing enzymes, drug transporters and drug targets to understand interindividual variability in drug clearance and responses in clinical practice and potential use in personalized medicine. Polymorphisms in the cytochrome P450 (CYP) family may have had the most impact on the fate of pharmaceutical drugs. CYP2D6, CYP2C19 and CYP2C9 gene polymorphisms and gene duplications account for the most frequent variations in phase I metabolism of drugs since nearly 80% of drugs in use today are metabolised by these enzymes. Approximately 5% of Europeans and 1% of Asians lack CYP2D6 activity, and these individuals are known as poor metabolizers. CYP2C9 is another clinically significant drug metabolising enzyme that demonstrates genetic variants. Studies into CYP2C9 polymorphism have highlighted the importance of the CYP2C9*2 and CYP2C9*3 alleles. Extensive polymorphism also occurs in a majority of Phase II drug metabolizing enzymes. One of the most important polymorphisms is thiopurine S-methyl transferases (TPMT) that catalyzes the S-methylation of thiopurine drugs. With respect to drug transport polymorphism, the most extensively studied drug transporter is P-glycoprotein (P-gp/MDR1), but the current data on the clinical impact is limited. Polymorphisms in drug transporters may change drug's distribution, excretion and response. Recent advances in molecular research have revealed many of the genes that encode drug targets demonstrate genetic polymorphism. These variations, in many cases, have altered the targets sensitivity to the specific drug molecule and thus have a profound effect on drug efficacy and toxicity. For example, the beta (2)-adrenoreceptor, which is encoded by the ADRB2 gene, illustrates a clinically significant genetic variation in drug targets. The variable number tandem repeat polymorphisms in serotonin transporter (SERT/SLC6A4) gene are associated with response to antidepressants. The distribution of the common variant alleles of genes that encode drug metabolizing enzymes, drug transporters and drug targets has been found to vary among different populations. The promise of pharmacogenetics lies in its potential to identify the right drug at the right dose for the right individual. Drugs with a narrow therapeutic index are thought to benefit more from pharmacogenetic studies. For example, warfarin serves as a good practical example of how pharmacogenetics can be utilized prior to commencement of therapy in order to achieve maximum efficacy and minimum toxicity. As such, pharmacogenetics has the potential to achieve optimal quality use of medicines, and to improve the efficacy and safety of both prospective and licensed drugs.

The CYP2A6 gene spans a region of approximately 6 kb pairs consisting of 9 exons and has been mapped to the long arm of chromosome 19 (between 19q12 and 19q13.2). The CYP2A6 protein has 494 amino acids and is an important hepatic Phase I enzyme that metabolizes approximately 3% of therapeutic drugs (n > 30; e.g. valproic acid, pilocarpine, tegafur, fadrozole, ifosfamide, cyclophosphamide, nicotine, tamoxifen, promazine, propofol, and cisapride), environmental toxicants (e.g. gasoline additives), and many procarcinogens such as nitrosamines and aflatoxin B(1). This enzyme also participates in the biotransformation of several endogenous compounds such as retinoid acids and steroids. Because CYP2A6 is responsible for 70-80% of the initial metabolism of nicotine, CYP2A6 has been proposed to be a novel target for smoking cessation. Site-directed mutagenesis and homology modeling studies have identified a number of amino acids (e.g. F300, A301, S208, S369, and L370) that play a role in substrate recognition and binding. CYP2A6 shows a crystal structure with a compact, hydrophobic active site with Asn297 serving as one hydrogen bond donor and orienting substrates for regio-selective oxidation. CYP2A6 contains the second smallest active site cavity among the human CYPs with known structures. The regulation mechanism of CYP2A6 expression is not fully understood, but available data suggest that several nuclear receptors including constitutive androstane receptor, pregnane X receptor and glucocorticoid receptor are involved in its regulation. Pilocarpine and tranylcypromine are commonly used as selective competitive inhibitors of CYP2A6. Selegiline, methoxsalen, (R)-(+) menthofuran and decursinol angelate are mechanism-based inhibitors of CYP2A6. Both in vitro and in vivo studies have demonstrated a wide (20- to >100-fold) interindividual variation in CYP2A6 expression and activity, which is due primarily to genetic polymorphisms in the CYP2A6 gene, but CYP2A6 activity is also modified by certain drugs and pathological and environmental factors. To date, more than 36 variant alleles (*1B through *37) of the CYP2A6 gene have been identified. There have been 278 SNPs found in the CYP2A6 upstream sequence, 8 introns and 9 exons in NCBI dbSNP. Polymorphism of CYP2A6 has been associated with smoking behavior, drug clearance and lung cancer risk. Further studies are warranted to explore the role of CYP2A6 in clinical practice, drug development and toxicology.