Cytochrome P450: CYP2C19*2

RDB2070

Determination of the "poor metabolizer" allele CYP2C19*2

Clinical Relevance

Phase 1 and 2 enzymes of the liver

Many drugs and endogenous compounds are metabolized via a small number of metabolic pathways by enzymes localized in the liver. Phase 1 reactions involve oxidation, reduction or hydrolysis. Enzymes of Phase 2 reactions conjugate by glucuronidation, sulphation, acetylation ect.. The result of all these reactions is the conversion of drugs into more polar, water-soluble compounds which can be easily excreted from the body (1).

There is a extensive inter-individual variation in human drug metabolism. Individuals can sometimes be divided in low, extensive, rapid or ultrarapid metabolizer. This can lead to therapeutic difficulties or even failure (2). The main cause for the variation in drug metabolism is genetic polymorphism of the genes of phase 1 and 2 enzymes. Polymorph means, there exist different alleles of a gene in a population.

Cytochrome P450

The genes for CYP2D6, CYP2C9, CYP2C19 and CYP2A6 are functionally polymorphic. Therefore approximately 40% of human P450 dependent drug metabolism is carried out by polymorphic enzymes (3) (for a list of all currently known cytochrome P450 gene alleles go to http://www.imm.ki.se/ CYPalleles/).

CYP2C19

Currently there are eight different alleles of the CYP2C19 gene described, of which seven code for inactive versions of the enzyme. The nomenclature for the wildtype allele is CYP2C19*1, the mutated alleles are CYP2C19*2 to *8 (6, http://www.imm.ki.se/CYPalleles/). Individuals can be characterized as extensive (EMs) metabolizers if at least one wildtype allele is present or poor metabolizers (PMs) if both alleles code for inactive enzymes (7). The CYP2C19 phenotype is measured through oral administration of S-mephenytoin. In individuals with the phenotype EM S-mephenytoin is quickly conjugated and excreted in the urine. In contrast, in PMs, virtually no hydroxylation occurs (8).

Between 2-5% of Caucasians are PMs for CYP2C19 catalysed drug metabolism, and about 20% of the asian population (6,7). In Asians the alleles CYP2C19*2 and *3 together accounts for 100% of the defective alleles. In the caucasian population 85% of the poor metabolizer are homozygous for the allele CYP2C19*2. The CYP2C19*3 to *8 alleles are extremly seldom. So for the remainig 15% of PMs additional defective alleles must be present (3,6,7).

The CYP2C19 genotype can seriously affect the success of drug therapy. In Patients with the PM phenotype the proton pump inhibitor omeprazole has a severly prolonged half-life (9). Patients heterozygous for a defective CYP2C19 allele displayed an improved cure rate for Helicobacter pylori infections during concomitant omeprazole and amoxicillin treatment (60% towards 28,6%; 10). Patients with two defective alleles had a cure rate of 100% (10).

Other important clinically used drugs that are affected by the CYP2C19 polymorphism are certain antidepressants, barbiturates, the anxiolytic diazepam and the antimalarial proguanil (1,8). The most important substrates of CYP2C19 are summorized in Table 1.