Genetic Basis of Drug Metabolism

Margaret K. Ma, Michael H. Woo, Howard L. Mcleod

Disclosures

Am J Health Syst Pharm. 2002;59(21) 

In This Article

Abstract and Introduction

Abstract

The application of pharmacogenetics in identifying single nucleotide polymorphisms (SNPs) in DNA sequences that cause clinically significant alterations in drug-metabolizing enzyme activities is discussed.

Recent advances in pharmacogenomic research have begun to elucidate the inherited nature of interindividual differences in drug-induced adverse reactions, toxicity, and therapeutic responses. In one particular area of study, variations in DNA sequences (i.e., genetic polymorphisms) explain some of the variability in drug-metabolizing enzyme activities which contribute to alterations in drug clearance and impact patients' response to drug therapy. Historical and current examples of several extensively studied SNPs include the genes encoding for glucose-6-phosphate dehydrogenase, N-acetyltransferase, and the superfamily of cytochrome P-450 (CYP) isoenzymes. Because CYP isoenzymes metabolize a large number of structurally diverse drugs and chemicals, most of the variant genotypes of the CYP2D6, CYP2C9, CYP2C19, and CYP3A families have been identified and studied. Individuals with aberrant genes for these enzymes may experience diminished efficacy or increased toxicity in response to certain drugs because of the different levels of activities associated with variant genotypes. The frequency of variant alleles for drug-metabolizing enzymes often differs among ethnic groups. Continued research in pharmacogenetics will further our understanding in interindividual differences in drug disposition. The application of this knowledge will ultimately help individualize drug dosing and drug therapy selection, predict toxicity or therapeutic failure, and improve clinical outcomes.

Pharmacogenetics has elucidated the genetic basis for interindividual variability in drug response and will continue to play a key role in defining strategies to optimize drug therapy.

Introduction

The term "pharmacogenetics" was first coined by Friedrich Vogel[1] in 1959, who defined it as the "study of the role of genetics in drug response." It is one of the most rapidly growing areas and is becoming increasingly important in clinical pharmacy. The pharmacogenetics of drug-metabolizing enzymes is a prominent focus of this field, because genetic makeup is responsible for a significant portion of drug-induced toxicity; many drugs are metabolized by enzymes that are encoded by polymorphically expressed genes.[2] Genotype analysis can be used to identify DNA changes in specific metabolic pathways that produce aberrant phenotypes. Hence, patients can be classified as extensive, intermediate, or poor metabolizers according to their ability to metabolize certain drugs. This classification can differentiate interpatient and intrapatient pharmacokinetic and pharmacodynamic variability;[3,4,5] however, not all genetic polymorphisms of drug-metabolizing enzymes are clinically relevant. The potential for a clinically significant event is enhanced if the drug is widely used and has a narrow therapeutic range, if the enzyme pathway plays a major role in the elimination of the drug, or if the number of therapeutic alternatives is limited. With increasing pharmacogenetic evidence, interindividual differences in drug-related toxicity and therapeutic response are no longer idiosyncratic. Although much work is needed to develop applications of pharmacogenetic information for daily patient care, many success stories illustrate how pharmacogenetics can be used to guide therapy. Eventually, pharmacogenetic information may become a routine tool for providing rational individualized therapeutics and patient care.

The pharmacogenetic differences in a number of phase-I enzymes, such as cytochrome P-450 (CYP) isoenzymes, dehydrogenases, and esterases, and phase-II (conjugating) enzymes have been extensively studied. This review introduces the concept of pharmacogenetics in the context of drug-metabolizing enzymes and highlights the polymorphisms in DNA sequences that lead to clinically significant alterations in drug-metabolizing-enzyme activities. Many of these genetic variants (i.e., genotypes) were discovered after observing adverse reactions (i.e., phenotypes) after administering common doses of drugs to patients. We have focused on the most common single nucleotide polymorphisms (SNPs), the inherited nature of their deficiency, their frequency, and the clinical importance of drug-metabolizing-enzyme variants. Most drug-metabolizing enzymes discussed in this review (e.g., CYP isoenzymes, N-acetyltransferase) are located primarily in the liver and, to a lesser extent, in other organs, such as the small intestine.

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