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 cytochrom P450 (CYP) family of heme monooxygenases comprise the
most important group of phase 1 enzymes. These enzymes oxidate a wide
range of endogenous as well as exogenous compounds using atmospheric
oxygen (O2) (4). The cytochrome P450 gene family contains 60 to 100
differents genes, of which only a small group is involved in drug
and chemical transformations (3). The most important P450 isoenzyme
is CYP3A4 (50% of the P450 metabolism) followed by CYP2D6 (20%), CYP2C9
and CYP2C19 (together 15%). The remaining is carried out by CYP2E1,
CYP2A6 and CYP1A2 (3,5).
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/).
CYP2C9
Beside the wildtype allele CYP2C9*1 there are two additional alleles
described, CYP2C9*2 und *3 (6, http://www.imm.ki.se/CYPalleles/).
In both mutated alleles a pointmutation leads to a substitution of
an aminoacid in the protein. In CYP2C9*2 an arginin at position 144
is converted to a cysteine (R144C), in CYP2C9*3 an isoleucine at position
359 is converted to a leucine (I359L) (6). The CYP2C9*3 variant is
less than 5% as efficient as the wildtype enzyme, while CYP2C9*2 shows
about 12% of wildtype activity (7,8). Under Caucasians about 19% are
heterozygous for CYP2C9*1/*2 and 3% homozygous CYP2C9*2/*2, 15% are
heterozygous CYP2C9*1/*3 and only 1% homozygous CYP2C9*3/*3 (6,9).
Cytochrome P450 CYP2C9 catalysis the metabolism of important drugs
such as phenytoin (antiepileptic), tolbutamide (antidiabetic), losartan
(angiotensin II receptor antagonist), warfarin (antikoagulant), diazepam
(anti-inflammatory) (3,6). A comprehensive list of all known substrates
including references can be found on the side http://medicine.iupui.edu/flockhart/.
Patients with venous and arterial thromoboembolic disorders are often
treated with the anticoagulant coumarin derivative warfarin. Beside
substantial improvements in oral anticoagulant therapy bleeding is
still a dreaded complication. The risk of serious haemorrhage during
warfarin therapy ranges from 1.3 to 4.2 % per 100 patient years of
exposure (10). It is difficult to predict the optimal dose for warfarin
therapy. The effective daily dose ranges from 0.5 mg to 60 mg (11).
The cause for this interindividual variation in the response to a
given dose of warfarin - ie the cause of hyper-responsiveness to small
doses - lies in the genotype of the cytochrome P450 CYP2C9 (11-13).
Aithal et al. (11) found that in a group of patients with a daily
warfarin dose requirement of 1.5 mg or less 81 % had one or more of
the variant alleles CYP2C9*2 or *3 present compared with 40 % in the
control group. The genetically determined high-reponders to warfarin
had bleeding complications four times more commonly than did a control
group stabilised on larger doses of the drug (11).
Genotyping of CYP2C9 identifys inidividuals who have an increased
risk of bleeding complications. The initial doses of warfarin should
be smaller for carriers of mutant alleles than the standard recommendation.
Knowledge of the CYP2C9 genotype may also help the clinician to decide
against the use of warfarin, particulary in high-risk elderly patients
and choice other coumarin derivatives which are not influenced by
CYP2C9 (11,14).
In the pharmaceutical industry patients involved in clinical trials
for the development of new drugs are already regulary genotyped in
order to obtain informations about pharmacokinetic properties and
observed side-effects (3). Informations about the genotype provide
the doctor with predictive information of the likelihood of successful
drug therapy and the possibility to individualize the drug dose of
the specific patient (3).
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