on approximately 25 percent of all clini- cally used medications. Cytochrome P450s (CYPs) comprise one
of the largest multi-gene families and are widely known for the diversity of chemical reactions they catalyze as well as the variety of substrates upon which they act. Of the 57 known CYPs, a mere six metabolize approximately 90 percent of clinically pre- scribed drugs. Tis diversity arose through gene duplication of the original cytochrome P450 gene, and different pressures allowed the generation of metabolic diversity in the gene family. It is presumed that many of the chemical reactions catalyzed by these cytochrome P450 enzymes are the result of animal life having to deal with various biologically active compounds encountered primarily from ingesting plants. Te original cytochrome P450 gene coded for an enzyme whose key role was detoxification of oxygen, which was new to Earth’s atmosphere at that time. Indeed, molecular oxygen is required for the function of CYPs, and is consumed in the reaction. Genetic variation within the DNA se-
quence (i.e., genetic polymorphisms and copy number variations) of cytochrome P450s can affect the structure, function and/or expression of the cytochrome P450 enzymes. Multiple polymorphisms affect the function of CYPs 2D6, 2C19 and 2C9. By performing a simple and low- cost panel of 50 or so SNPs, patients are deemed poor (PM), intermediate (IM), normal (NM), Extensive (EM) or ultra- rapid (UM) metabolizers. Adverse drug reactions (ADRs) are the
third leading cause of death in the U.S. Many ADRs are avoidable when the geno- type of the patient is known, as more than 75% of the population has known genetic variations that increase their propensity for ADRs. In addition, genetic variants that affect drug metabolism can exacerbate drug-drug interactions (adverse drug reac- tions that occur when the patient is taking multiple drugs at the same time) a frequent
www.datia.org datia focus 51
Figure 3. In those patients where a gene mutation results in poor metabolism of a certain family of drugs, the body is unable to metabolize or eliminate the target drug from the system. Each succeeding dose will add to the circulating drug level, where a toxic effect from that drug will be displayed.
Figure 4. Some genetic variations result in a metabolic enzyme that functionally metabolizes a drug much more rapidly than normal, or in some cases extra copies of a gene will cause to metabolic system to rapidly remove the drug from your bloodstream prior to achieving the intended therapeutic benefits.
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