CYP450 Enzyme System
To grasp the basics of pharmacogenetics, you need to understand drug metabolism—specifically the cytochrome P450 (CYP450) enzyme system. CYP450 enzymes are the most important drug-metabolizing enzymes, and the CYP450 enzyme system is the most important system affecting drug metabolism. Other genetic factors (not discussed in this article) also affect drug transport proteins, drug absorption, drug receptors, and drug excretion. (See CYP450 enzymes: What and where they are.)
Polymorphism and Drug Response
Wide individual variations exist in the expression and function of CYP450 enzymes. Research shows genetic variation, or polymorphism, in these enzymes is one of the most important causes of variable drug response. These variations result from single nucleotide polymorphisms (SNPs).
The nucleus of every cell contains 23 pairs of chromosomes, which are made up of DNA strands. In turn, DNA consists of nucleotides composed of bases (adenine, cytosine, guanine, and thymine). Normally, these bases occur in specific sequences.
The gene is the DNA segment responsible for directing the production of a specific protein. When the normal sequence of bases changes (that is, when SNP occurs), the gene's function alters—and so does the function of the protein for which that gene is responsible. In this case, the protein is part of a CYP450 enzyme. A specific gene is associated with and encodes each CYP450 enzyme.
Polymorphism can determine how well a CYP450 enzyme metabolizes a drug—or whether it metabolizes it at all. Depending on the genetic makeup of the CYP450 enzyme system a person has inherited, the metabolic activity of a particular CYP450 enzyme can be categorized as poor, intermediate, extensive, or ultra-rapid. Correspondingly, some people are considered normal metabolizers of drugs, others are intermediate metabolizers, still others are poor metabolizers (experiencing no clinical effect from the drug), and some are ultra-rapid metabolizers (experiencing toxic drug effects).
Polymorphism and Drug Interactions
CYP450-enzyme polymorphism is crucial not just in terms of how it affects drug performance but in how drugs affect the enzymes. A particular drug may inhibit or induce (enhance) the metabolic activity of a certain CYP450 enzyme; if that enzyme is involved in metabolizing a second drug the patient takes, the second drug may not work. In other words, one drug's effect on CYP450 enzymes may disrupt another drug's metabolism. When enzymatic activity is inhibited, a drug's concentration may rise to toxic levels, and more numerous and more serious adverse effects may occur. Conversely, when enzymatic activity is induced, drug concentration may decrease, severely limiting drug efficacy.
Am Nurs Journal. 2011;6(5):23-28. © 2011 HealthCom Media
Cite this: Drug Therapy Gets Personal with Genetic Profiling - Medscape - May 01, 2011.
