Pharmacogenomics and its applications

Medical Laboratory Observer, March, 2005 by Robert M. White, Steven H.Y. Wong

A clear example of how a protein and a mutation of that protein can affect a drug's absorption, however, is found with the cardiac glycoside digoxin. P-glycoprotein, which is a membrane protein that functions as an exporter of xenobiotics from cells, is a product of the MDR1 gene. Although several models have been proposed for P-glycoprotein's action, basically P-glycoprotein acts to move xenobiotics from epithelial cells into the adjacent lumen. P-glycoprotein is found in numerous cells associated with excretory function. In the case of digoxin (and certain other drugs), reduced intestinal absorption of the drug can be associated with induction (increased amounts) of the enzyme or the C3435T (where the deoxyribonucleotide cytidine replaces the deoxyribonucleotide thymidine at position 3435 in the DNA sequence that codes P-glycoprotein) mutation of P-glycoprotein. Thus, the mutant form of the protein causes a lowered overall intestinal absorption of digoxin by excreting more back into the intestinal lumen than the wild-type protein. (17)

Once a drug has entered the bloodstream, it is transported to various parts of the body where the drug may be activated or inactivated by certain enzymes (vide infra) by a process commonly referred to as biotransformation--or metabolism; be excreted unchanged; interact with a receptor or other location where the desired (and, sometimes, undesired or side-effect) action(s) may take place; or be stored (e.g., the retention of [[DELTA].sup.9]-tetrahydrocannabinol or THC in body fat or lead in bone) for future uses such as those previously described. Many drugs and other xenobiotics express their pharmacodynamic action by interacting with a specific protein receptor. As an example, morphine acts at what are called [mu] receptors. Indeed, polymorphism is exhibited by the various opiate receptors. (18)

Perhaps the best-characterized and most extensively studied area in pharmacogenomics is biotransformation. Fundamentally, biotransformation can be divided into two areas--Phase I and Phase II. Both Phase I and Phase II are designed to make xenobiotics more polar and, thus, more water-soluble. By being more polar and more water-soluble, metabolites are more easily excreted into excretory fluids such as urine. Phase I reactions include hydrolysis, reduction, and oxidation. Phase I biotransformation may activate a drug (known in this case as a prodrug) into a biologically active form or may inactivate an active drug. An example of activation is seen with the conversion of Tegafur into the active anticancer agent 5-fluorouracil (5-FU). An example of deactivation is seen with the oxidation of ethanol into acetaldehyde by alcohol dehydrogenase and the further oxidation of acetaldehyde into acetate by aldehyde dehydrogenase. Phase II biotransformation may or may not be preceded by Phase I biotransformation. Phase II biotransformation reactions involve glucuronidation; sulfation; acetylation; methylation; conjugation with glutathione; and conjugation with amino acids such as glycine, taurine, and glutamic acid. (19)