CYP2D6 polymorphism and its clinical significance

CYP2D6 je najopsežnije istražen polimorfni enzim koji sudjeluje u metabolizmu lijekova. Gen CYP2D6 je visoko polimorfan te je do danas otkriveno barem 112 alelnih varijanti koje kodiraju za inaktivni enzim, enzim sa smanjenom, normalnom ili povećanom enzimskom aktivnosti. Ovisno o kombinaciji alela i sposobnosti metabolizma lijekova, razlikujemo četiri metabolička fenotipa. Fenotip brzog metabolizma (EM) se smatra normalnom karakteristikom najvećeg dijela populacije, a javlja se u osoba s dva potpuno aktivna alela. Pojedinci s deficitom enzima (5 – 10 % pripadnika bijele rase) klasificiraju se kao spori metabolizatori (PM). Karakterizira ih nedostatak aktivnog alela te posljedično smanjena aktivnost enzima kodiranog tim alelom što rezultira nakupljanjem lijeka u organizmu i povećanim rizikom od pojave neželjenih učinaka lijeka. Među ostalima je enzimska aktivnost veoma varijabilna te se kreće od ekstremno visoke u vrlo brzih metabolizatora do smanjene u srednjih (intermedijarnih) metabolizatora. Osim značajne interindividualne varijbilnost, zabilježena je i značajna međuetnička varijabilnost u raspodjeli alelnih varijanti CYP2D6 koja podrazumijeva i postojanje "populacijski specifičnih" alelnih varijanti. Usprkos niskoj zastupljenosti enzima CYP2D6 (2 – 4 %) u odnosu na druge jetrene enzime CYP, ovaj enzim sudjeluje u biotransformaciji otprilike 20 – 25 % lijekova dostupnih na tržištu. Enzim CYP2D6 sudjeluje u metabolizmu velikog broja klinički značajnih lijekova, uključujući opioide (kodein, tramadol), antidepresive (amitriptilin, imipramin, fluoksetin, mianserin, venlafaksin), antipsihotike (aripiprazol, haloperidol, olanzapin, risperidon), antitustike (dekstrometorfan), β-blokatore (metoprolol, bufuralol, propranolol), protutumorske lijekove (tamoksifen) i antiemetike (ondansetron i tropisetron). Genotipizacija CYP2D6 je jedan od alata koji se koriste prilikom provođenja personaliziranog liječenja, što rezultira povećanjem djelotvornosti terapije i smanjenjem troškova liječenja. Procjenjuje se da bi takav personalizirani pristup liječenju na temelju genetskih značajki mogao biti relevantan za terapiju s 10 – 20 % lijekova. U ovom radu se razmatra utjecaj genetske varijabilnosti CYP2D6 na klinički ishod i terapijski učinak lijekova-supstrata CYP2D6.CYP2D6 is the most extensively studied polymorphic drug-metabolizing enzyme. CYP2D6 gene is highly polymorphic with at least 112 allelic variants discovered so far which encode an inactive enzyme, enzyme with reduced, normal or increased enzyme activity. Subjects are classified into four metbolic phenotype groups, depending on combination of alleles and the ability to metabolise xenobiotics. Extensive metabolism (EM) is considered to be a characteristic of the normal population and is found in subjects with two fully functional alleles. Individuals who are poor metabolisers have no active alleles and, therefore, lack functional enzyme activity which, consequently, results in accumulation of specific drug substrates and adverse drug reaction (ADR) occurrence. Among other subjects, enzyme activity is highly variable and ranges from extremely high in ultrarapid metabolizers to reduced in intermediate metabolizers. Apart from significant interindividual variability, a significant interethnic variability in distribution of CYP2D6 allelic variants has also been described, including existence of ‘population-specific’ allelic variants. Although CYP2D6 constitutes only 2 – 4 % of the total hepatic CYPs, it is one of the most important drug metabolizing enzymes due to its role in biotransformation of approximately 25 % of clinically used drugs. CYP2D6 enzyme is involved in the metabolism of numerous clinically significant drugs including opioids (codeine, tramadol), antidepressants (amitriptyline, imipramine, fluoxetine, mianserin, venlafaxine), antipsychotics (aripiprazole, haloperidol, olanzapine, risperidone), antitussives (dextromethorphan), beta-blockers (metoprolol, bufuralol, propranolol), anticancer drugs (tamoxifen) and antiemetic drugs (ondansetron i tropisetron). Genotyping of CYP2D6 is one of the tools used for implementation of personalized drug treatment which results in increased drug efficacy and decreased cost of ADR treatment. It is estimated that such personalized gene-based treatment could be relevant for 10 – 20 % of all drug therapy. In this thesis, the impact of the CYP2D6 genetic variability on the clinical outcome and therapeutic and/or adverse effects of drug-substrates of CYP2D6 is reviewed