Cytochrome P450 2d6

The CYP2D6 gene is a very polymorphic gene with more than 70 alleles described today.[1,2] This diversity leads to a great variety of activity of the enzyme debrisoquine 4-hydroxylase, which is encoded by the CYP2D6 gene. Many popular drugs such as antidepressants, neuroleptics, or cardioactive drugs, e.g., amitriptyline, paroxetine, haloperidol, metoprolol, etc.,[3] are substrates of CYP2D6. This may lead to adverse drug effects or therapy resistance. Subjects with normal enzymatic activity are called extensive metabolizers (EM). Subjects with increased activity are termed ultraextensive and ultrarapid metabolizers (UM), respectively, and have a prevalence of 1-10% in a Caucasian population.1-4-1 They often do not reach therapeutic drug concentrations and suffer from therapeutic failure. Individuals with low or absent activity run the risk of potentially increased drug concentrations and adverse drug reactions. They are named poor metabolizers (PM) and can be found in approximately 7% of Caucasians.1-5-1 This last group has to be distinguished from subjects with impaired but residual function, called intermediate metabolizers (IM). Substantial ethnic differences are observed regarding the frequency of the different phenotypes.[6]

The high number of polymorphisms with functional consequences results in complex and time-consuming genotyping procedures requiring extensive manpower and making it difficult to employ these methods in a time-critical clinical setting.

Real-time PCR offers substantial benefits in that regard. It is much faster than conventional PCR with subsequent restriction enzyme digestion and gel electrophoresis. Further advantages are lower risk of DNA contamination, facilitated handling, automated data processing, and the lack of toxic reagents such as ethidium bromide.

In different ethnic populations, it is possible to restrict testing to a limited set of alleles without sacrificing appreciable sensitivity of the assay (for details of the different alleles, see Table 1).

In a Caucasian population, six alleles, in detail *3, *4, *5, *6, *7, and *8, cause up to 99% of all PMs.[7] Up to 50-60% of all IMs can be predicted by the additional detection of the —1584 C/G polymorphism of the promoter, which encodes for the *2 and *41 alleles.[8] Duplicated or multiplicated functional CYP2D6 genes account for 10-30% of all UMs.[9] Other UMs may be explained by the *35 allele,[10] but this has been questioned by an in vitro analysis.[11] Taken together, genotyping of less than 10 polymorphisms of the CYP2D6 gene is sufficient to classify the vast majority of subjects in a Caucasian population.

Combining a fast method and a choice of polymorphisms, a comprehensive analysis can be carried out in one working day with a hands-on time of 3-4 hr,[12] employing a long PCR of the CYP2D6 gene on the LightCyclerâ„¢ as a preamplification step. A preamplifi-cation step is necessary to detect both deletion and duplication as well as to avoid confusion from the two pseudogenes CYP2D7 and CYP2D8.[13] Furthermore, the same study reported the detection of *2, *35, and *41 alleles by hybridization probes and melting curve analysis

Table 1 CYP2D6: Alleles, nucleotide changes, and enzyme activity
Getting Started With Dumbbells

Getting Started With Dumbbells

The use of dumbbells gives you a much more comprehensive strengthening effect because the workout engages your stabilizer muscles, in addition to the muscle you may be pin-pointing. Without all of the belts and artificial stabilizers of a machine, you also engage your core muscles, which are your body's natural stabilizers.

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