Feng, Xiaodong_ Xie, Hong-Guang - Applying pharmacogenomics in therapeutics-CRC Press (2016)

Pharmacogenomics and Laboratory Medicine
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and bioactivation of the prodrug. Sometimes, phase I metabolism could generate
an intermediate metabolite in the inactivation and degradation of the drug. Phase II
metabolism often produces a more easily excreted water-soluble compound through
conjugation reactions, such as acetylation, glucuronidation, or sulfation. Last, in
phase III, the conjugated drugs may be further processed, before being recognized
by efflux transporters and pumped out of the cell. Genetic differences affect many
steps in drug metabolism pathways. One of the most extensively studied pharmacokinetic
examples is the CYP superfamily (Guengerich 2008; Zanger et al. 2008).
The CYP superfamily is a group of isoenzymes, primarily expressed in the hepatocytes
and enterocytes, but also found in any other cells throughout the body. Inside
the cell, the P450 enzymes are located in the endoplasmic reticulum and mitochondria.
The mitochondria is the energy-producing center of the cell, and the CYP
enzymes located in the mitochondria are generally the terminal oxidase enzymes in
electron transfer chains. In contrast, the CYP enzymes located in the endoplasmic
reticulum are involved in metabolizing a broad variety of drugs by catalyzing oxidative
or reductive reactions.
The CYP enzymes are encoded by the superfamily of CYP genes (the gene name
is italicized as required). There are approximately 60 CYP genes in the human
genome that are classified into 18 families and 44 subfamilies based on sequence
homology. * Among these families, the CYP1 to 3 families are responsible for the
major phase I drug metabolism, and the CYP4 to 51 are associated with endobiotic
metabolism. In this section, we will discuss the genetic polymorphisms of
some major players in pharmacokinetics, including CYP2D6, CYP2C9, CYP2C19,
CYP3A4, and CYP3A5. The number immediately following the CYP indicates the
gene family, the capital letter indicates the subfamily, and the last number following
the capital letter indicates the individual gene. The number after * indicates the
allele (see the following section for examples).
The phenotypic distribution of genetic polymorphisms in a population for the
CYP genes as well as other monogenes involved in pharmacokinetics may exhibit
gene dosage effects. There are generally three types of genetic phenotype distributions
associated with drug response: bimodal, multimodal, or broad without an
apparent antimode. The bimodal phenotypic distribution exhibits continuous probability
distribution with two different modes appearing as distinct peaks. An example
of bimodal phenotypic distribution is NAT2 manifesting as fast acetylator or slow
acetylator. The multimodal distribution has two or more modes. An example of multimodal
phenotypic distribution is CYP2D6 four distinct metabolizers (Ingelman-
Sundberg et al. 2007; Zanger et al. 2004). The broad distribution has no apparent
mode and an example is CYP3A5.
CYP2D6
The CYP2D6 enzyme is responsible for the oxidative metabolism of up to 25% of
commonly prescribed drugs, including the antidepressants, antipsychotics, opioids,
antiarrhythmic agents, and tamoxifen. Many drugs metabolized by this enzyme
* www.http://drnelson.uthsc.edu/human.P450.table.html