Principles Of Pharmacogeneticspharmacogenomics

The basic principles of pharmacogenetics and pharmacogenomics have been reviewed in depth by recent articles and chapters (4-11). According to the central dogma of molecular biology, the genetic code of DNA is passed through transcription, onto mRNA. The information in mRNA is passed through translation, in protein synthesis. These proteins may be drug metabolizing enzymes, transporters, and receptors. As a result, DNA genetic variations would determine the enzyme activity, or transporters and receptor sensitivity. For drug metabolizing enzyme, the lack of and the presence of genetic variation would result in normal to deficient or higher enzyme activities. Genetic variations might include SNPs, deletion, duplications, and other variations. The polygenic determinants of drug response are illustrated in Fig. 3

Fig. 3. Polygenic determinants of drug response (10). (With Permission from ref. 10, Copyright 2003 Massachusetts Medical Society).

Fig. 4. Pharmacogenetics of CYP 2D6 (32). Reprinted with permission.

Debrisoquin:4-Hydroxydebri$oquin Metabolic Ratio

Fig. 4. Pharmacogenetics of CYP 2D6 (32). Reprinted with permission.

[according to Evans and McLeod (10)]. By comparing an individual with two wild-type alleles, an extensive metabolizer, on the left to an individual with two variant alleles, and a poor metabolizer, on the right, the genetic variations would result in lower enzymes activity and elevated area under curve (AUC) with corresponding increased toxicity and decreased receptor sensitivity and efficacy. The heterozygous individual in the middle with one variant allele, an intermediate metabolizer, with resultant AUC, toxicity and efficacy intermediate between those of the extensive and poor metab-olizers. With a possible combination of nine metabolism and receptor genotypes, the therapeutic index would range from 13 to 0.125. Furthermore, individuals with multiple copies of the genes correspond to ultra-rapid metabolizers, and Fig. 4 shows the debrisoquin metabolic ratios of these phenotypes (32).

This relationship might be readily further conceptualized by a pharmacology triangle, proposed by Linder and Valdes, Jr. Pharmacogenomics provides the fundamental basis, the independent variable for the two interrelated, dependent variables pharmacokinetics (drug metabolism) and pharmacodynamics (drug action) (33).

Pharmacology triangle

Pharmacology triangle

Ph.irmacogenomics

Reprinted with permission.

Weinshilboum reviewed the pharmacogenetics of phase I drug metabolism enzymes including cytochrome P450 (CYP) 2D6, 2C9, 2C19, dihydropyrimidine dehydrogenase, and butyrylcholinesterase and phase II enzymes N-acetyltransferase 2, uridine diphosphate-glucuronosyltransferase 1A1, thiopurine S-methyltransferase, and catechol O-methyltransferase (9). Evans and McLeod reviewed the effect of polymorphism of drug target gene on drug effect—angiotensin-converting enzyme, arachidonate 5-lipoxygenase, ^2-adrenergic receptor, bradykinin B2 receptor, dopamine receptors, estrogen receptor-a, glycoprotein, and serotonin transporter—and the effect of polymorphism in disease, or treatment-modifying genes—adducin, apolipoprotein E, HLA, cholesterol ester transfer protein, ion channels, methylguanine methyl transferase, parkin, prothrombin and factor V, and stromelysin-1 (10). Wong and Jannetto (34) supplemented the information in a recent publication.

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