Navigation Links
Gene Chips to Detect CYP Variations: A New Step Toward Customized Medical Therapy.


Michael S. Singer, M.D., Ph.D.
Contributing Editor
Harvard Medical School

The FDA approval of BiDil for heart failure in African American patients has underscored the concept that two patients can respond differently to the same medication. This concept holds true for a wide variety of everyday medications, and in many cases is due to individual genetic variations. As the field of pharmacogenetics focuses on these issues, valuable new laboratory tools have arrived to help clinicians apply pharmacogenetic knowledge to patient care.

Probably the most important gene family to govern individual drug responses, CYP (also called cytochrome P450) oxidases are a diverse family of enzymes that metabolize compounds unfamiliar to the body. Concentrated in liver cells, they modify the chemical structure of drugs shortly after they are absorbed from the gastrointestinal tract. The chemical modification renders them more water soluble and hence more easily excreted. Six CYP enzymes (named 1A2, 2C9, 2C19, 2D6, 2E1, 3A4) account for over 90% of drug metabolism (but do not appear to account for the selectivity of BiDil). Since a patient can take several concurrent medications metabolized by the same CYP enzyme, it should come as no surprise that CYP-related drug interactions are common. Clinicians are generally aware of these interactions, which either involve inhibition (competition) between two or more medications for the same enzyme, or induction (increase) of a particular CYP enzymes activity in response to a particular medication. In the former scenario, blood concentrations and the risk of side effects can rise to perilous levels; in the latter, concentrations can decline to the point that therapeutic value is lost.

Patients can also carry mutations or duplications in one or more CYP enzymes. Usually unbeknownst to the clinician, these polymorphisms can have pronounced effects on a patients ability to met abolize particular medications. As a result, patients can be classified as poor, intermediate, extensive, or ultra-rapid metabolizers. These conditions are relatively common, with prevalences that vary across different races. Similar to the scenarios described above, these patients are at risk for abnormal blood concentrations: poor metabolizers may develop serious side effects, and extensive or ultra-rapid metabolizers may be insufficiently treated.

Recent advances in microarray (gene chip) technology have made it possible to screen patients thoroughly for genetic variations in CYP enzymes. The AmpliChip CYP450 Test (Roche Diagnostics) detects mutations in two important CYP subtypes. The first, CYP2D6, metabolizes a number of medications, including antidepressants, anti-psychotics, anti-arrhythmics, and beta-blockers. The second, CYP2C19, metabolizes anticoagulants, anticonvulsants, proton pump inhibitors, benzodiazepines, anti-malarials, and other medications. The literature has shown that a genotype screen, such as the AmpliChip CYP 450 Test, can detect up to 90% of poor metabolizers at risk for overdoses.

High density microarrays, such as the one used by the AmpliChip CYP450 test, provide a versatile, miniaturized means to screen for multiple nucleic acid products in a rapid and parallel fashion. To build the microarray, small DNA fragments, also called probes, are anchored and synthesized at specific locations on a small, coated quartz surface. Different probes can be attached to different locations. Each probe is chosen to hybridize selectively with a specific DNA fragment. In the case of AmpliChip CYP450 test, this provides the ability for particular probes to bind portions of wild-type or mutant sequences from CYP2D6 and CYP2C19. The microarray is also constructed in a way that can detect duplications of a particular allele.

The actual test is carried out with a patient blood sample. The first step is to amplify CYP2D6 an d CYP2C19 gene products, which are then applied to the AmpliChip microarray and hybridized. The microarray is then washed, stained, and finally scanned. Computer software then interprets the optical pattern on the scan, which indicates the particular probes bound by the patients DNA sample. The software can then determine the patients genotype and predict a phenotype.

The GeneChip System 3000Dx (Roche Diagnostics) is a dedicated microarray system that supports the AmpliChip CYP450 Test. It includes a fluidics system, microarray scanner, workstation and software to carry out all of the steps outlined above. Other compatible products microarrays are expected in the future from Roche Diagnostics and its partner, Affymetrix. Companies such as Nanogen also continue to develop a number of microarray-based tools. Together, these advances will make tailored drug therapy a reality, and patients will benefit from more consistent phamacodynamics with fewer side effects.
'"/>




Related medicine technology :

1. Fast, Accurate Influenza A/B Antigen Detection
2. New Assays to Detect Disseminated Fungal Infections

Post Your Comments:
*Name:
*Comment:
*Email:
(Date:12/5/2016)... , Dec. 5, 2016 ... hydroxyurea (HU) in Complete Hematologic Response (CHR) ... ropeginterferon alfa-2b versus HU AOP will submit ... CONTINUATION-PV to obtain European marketing authorization in the coming months ... the FDA as it seeks approval for commercialization in the ...
(Date:12/4/2016)... 2016 Sickle cell disease (SCD) is an ... cells that get stuck in veins and block blood ... and complications leading to death. Each year, approximately 300,000 ... most of them lack access to comprehensive care or ... therapy for SCD, a pill called hydroxyurea approved more ...
(Date:12/2/2016)... SILVER SPRING, Md. , Dec. 2, 2016 /PRNewswire-USNewswire/ ... a new indication for Jardiance (empagliflozin) to reduce the ... 2 diabetes mellitus and cardiovascular disease. ... adults with type 2 diabetes mellitus," said Jean-Marc ... Metabolism and Endocrinology Products in FDA,s Center for Drug ...
Breaking Medicine Technology:
(Date:12/4/2016)... , ... December 04, 2016 , ... ... major cosmetic surgery can now take advantage of a cosmetic procedure known as ... rejuvenation treatment that reduces the appearance of age spots, fine lines, uneven ...
(Date:12/4/2016)... ... December 04, 2016 , ... Responsible dental care hinges ... brush properly to achieve optimal results. This important necessity inspired an inventor from Las ... a way to ensure that people break or avoid bad techniques of brushing the ...
(Date:12/2/2016)... ... ... Lori G. Cohen and Sara K. Thompson , shareholders in global ... Institute’s 21st Drug & Medical Device Litigation Conference , taking place in New York ... who chairs the firm’s Pharmaceutical, Medical Device & Health Care Litigation Practice and the ...
(Date:12/2/2016)... ... December 02, 2016 , ... On Dec. 2, 2016, CURE® magazine will host ... honoring the 2016 MPN Heroes—eight individuals who have made a difference in the field ... the standard of care, demonstrating leadership within the MPN community and/or a commitment to ...
(Date:12/2/2016)... Dothan, AL (PRWEB) , ... December 02, 2016 ... ... leaders from across the Dothan-Wiregrass Area in Alabama are expected to attend the ... Mike Schmitz, will help provide scholarship funds for area students and operating support ...
Breaking Medicine News(10 mins):