By DFK | October 16, 2013 at 08:34 AM EDT | 12 comments
In the previous post we discussed different 'metabolizer phenotypes' related to the specific drug metabolizing enzyme CYP2C19. Phenotype means how we 'express' our genetics. Some people express their genetics related to drug metabolism as 'poor metabolizers (PM)', meaning they have 'slow', decreased, or even absent metabolism, these individuals typically require lower doses of active drugs that are metabolized by the given enzyme. If the drug is a prodrug, and requires activation, a higher dose of the prodrug may be required, or another drug can be used. Some people are 'intermediate metabolizers (IM)', meaning that they have decreased metabolism relative to normal metabolism. These individuals typically require a lower dose of an active drug also, but not as low of a dose as a PM would require. Here, a prodrug may not work as well either as less drug would be activated. Some people are ultrarapid metabolizers (UM)', meaning they have increased metabolism relative to normal metabolism. These individuals typically require higher doses than a PM or IM and even a 'normal metabolizer'. These individuals can readily convert a prodrug to its active form. However, most individuals have a 'normal (extensive) metabolizer (EM)' phenotype. This has been called extensive metabolism, but that term can cause some confusion, so think of extensive as 'normal'.
As you will see, there are many different drug metabolizing enzymes. Some of these enzymes metabolize a relatively large percentage of drugs. The family of CYP (cytochrome P450) genes includes CYP2C19, as mentioned before, and CYP2D6, CYP2C9, and many others.
As you have seen, we utilize the star '*' nomenclature (e.g., *1/*2) to identify the two genes each person has (one from each parent) in what we call a genotype or diplotype (two genes). The '*' forms represent different genetics as introduced by a SNP (see post on September 04, 2013 at 7:56 AM EDT) or some other genetic variation. It is important to understand that the '*' nomenclature does not define phenotype the same way for each CYP. So, here is a challenge! The two links below are to current literature (Clinical Pharmacogenetic Implementation Consortium (CPIC) guidelines), which defines metabolism phenotype based on the '*' nomenclature. Below are some diplotypes for CYP2C19 and CYP2D6. In you post, define the phenotypes based on the diplotypes, here relating the genetics to metabolism. Note in your post, only provide two examples and leave the others for the next 'poster'. Thanks!
CYP2C19 Genotypes (example diplotypes; click HERE; read the table carefully):
CYP2D6 Genotypes (example diplotypes; click HERE; read the table carefully):
So, 'have at it' and we will learn something about this '*' nomenclature!