Textbook of Personalized Medicine - Second Edition [2015]

103

Pharmacogenetics of Phase I Metabolism

The most important of these enzymes is the CYP450 group.

CYP450

The cytochrome P450 enzyme system consists of a large family of proteins, which
are involved, in the synthesis and/or degradation of a vast number of endogenous
compounds such as steroids, cholesterol, vitamins and retinoic acid, as well as the
metabolism of exogenous toxins. P450 enzymes can alter, abolish or enhance drug
metabolism. There are likely more than 100 P450 genes that control these enzymes.
The most frequent change observed in CYP2D6 is a polymorphism that results in an
aberrant RNA splice event, which causes truncation and inactivation of the protein.
AmpliChip CYP450 (Roche) enables clinical diagnostic laboratories to identify
polymorphisms in two genes CYP2D6 and CYP2C19.
More than 50 % of the clinically used drugs are cleared through the action of
P450 enzymes: CYP2D6 and CYP3A4 metabolize majority of these. Because cyto-
chrome P450s play key roles in regulating important physiological processes, they
are also attractive targets for drug discovery. Inhibitors of P450 enzymes are used
clinically or are under evaluation for treatment of a number of diseases. Examples
of genetic variations seen in three of the CYP450 enzymes and the clinical impact
of those variations are shown in Table 4.2.
Clinically relevant genetic polymorphisms have been found in cytochrome P450-
mediated oxidation of debrisoquine and sparteine (CYP2D6), which represents
25 % of the major isoforms of P450 responsible for drug metabolism. Frequency
distribution of drugs metabolized by major CYP450 isoforms is shown in Table 4.3.
Commonly prescribed medications, which are metabolized by CYP2D6, are shown
in Table 4.4.

Table 4.1 Enzymes relevant to drug metabolism

Phase I enzymes (predominantly oxidative) Phase II enzymes (conjugative)
Alcohol dehydrogenase N-acetyl transferase 2
Cytochrome P (pigment)-450 (cyp) with
subtypes

Catechol O-methyltransferase

Dyhydropyrimidine dehydrogenase Glutathione-S-transferase and variants
Epoxide hydrolases Sulfotransferases and variants
Flavine-dependent monooxygenase 3 Thiopurine S-methyltransferase
NADPH-quinone oxidoreductase Thiopurine S-methyltransferase
Pseudocholinesterase (butyrylcholinesterase) Uridine diphosphate-glucuronosyltransferase
1A1
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Role of Pharmacogenetics in Pharmaceutical Industry