Polymorphism of CYP2C19 in patients with cardiovascular incident

Abstract

CYP2C19 je hemoprotein koji sudjeluje u prvoj fazi biotransformacije ksenobiotika i endogenih molekula te spada u veliku gensku obitelj CYP2C. U ukupnom udjelu metabolizma prve faze biotransformacije zajedno sa CYP2C9 čine 15 %. Lokus gena CYP 2C19 nalazi se na kromosomu 10q24 i sastoji se od 9 egzona. Gen koji kodira ovaj enzim je polimorfan što je značajno za kliničku praksu jer enzim CYP2C19 sudjeluje u metabolizmu više važnih lijekova. Genetički polimorfizam CYP2C19 česta je pojava u općoj populaciji sa značajnom međuetničkom varijabilnosti u učestalosti fenotipova. Tako je u bijeloj populaciji incidencija sporih metabolizatora 1-5%, 13-23% u azijata, 6% među Etiopljanima, te 70% među stanovništvom Vanuatu. Dosadašnja istraživanja navode zastupljenost CYP2C19*2 i CYP2C19*3 u 95 % osoba sporih metabolizatora. Najčešći polimorfni alel u bjelačkoj populaciji je alel 2C19*2, a u azijatskoj alel 2C19*3 koji kodiraju inaktivni enzim. Bitniji protektivni čimbenici u očuvanju integriteta endotela krvnih žila i hemostaze su produkti arahidonske kiseline (AK) poput epoksieikosatrienoične kiseline (EET) koja nastaje metabolizmom AK putem enzima CYP. Mutirani aleli CYP2C19*2 i CYP2C19*3 kodiraju enzim sa smanjenom katalitičkom funkcijom što dovodi do smanjenja koncentracije EETs-a i porasta koncentracije proupalnih citokina (IL-6 i hs-CRP) posljedično tome do ubrzanog razvoja i progresije ateroskleroze koja je glavni etiološki čimbenik kardiovaskularnih i neurovaskularnih bolesti (AKS, MU). Jedan od supstrata enzima CYP2C19 je i lijek klopidogrel, koji sprječava agregaciju trombocita i razvoj tromboze stoga se koristi u primarnoj i sekundarnoj prevenciji kardiovaskularnih i kardioembolijskih događaja (npr. CE MU). Povećan rizik za razvoj tih poremećaja dovodi se u svezu s genetičkom rezistencijom na klopidogrel kao posljedica prisutnosti bar jednog varijantnog alela CYP2C19*2/*3.CYP2C19 is a hemoprotein participating in the first phase of biotransformation of xenobiotics and endogenous molecules and represents a large gene family CYP2C. The total share of the first phase of metabolic biotransformation with CYP2C9 make up 15%. CYP2C19 gene locus is located on chromosome 10q24 and consists of 9 exons. The gene encoding this enzyme is polymorphic and it is important for clinical practice because of the CYP2C19 enzyme involved in the metabolism of several important drugs. Genetic polymorphism of CYP2C19 is common in the general population with significant inter-ethnic variability in phenotype distribution. The incidence of slow metabolizers is 1-5%, 13-23%, 6% and 70% in Caucasian, Asian, Ethiopian, and Vanuatu population respectively. Previous researches suggest the presence of CYP2C19*2 and CYP2C19*3 in 95% of slow metabolizers. The most common polymorphic allele in the Caucasian population is allele 2C19*2 and 2C19*3 allele in Asian population encoding the inactive enzyme. Some of the most important protective factors in preserving the integrity of endothelium in blood vessels and hemostasis are products of arachidonic acid (AA), such as epoksieicosatrienoic acid that is metabolised by CYP enzymes. Mutant alleles CYP2C19*2 and CYP2C19*3 encode an enzyme with reduced activity that results in reduced concentration of EETs and increased concentration of proinflamatory cytokines (IL-6 and hs-CRP) consequently leading to rapid development and progression of atherosclerosis, which is a major etiologic factor of cardiovascular and neurovascular diseases (ACS, stroke). One of the substrates of CYP2C19 enzyme is antiplatelet drug clopidogrel, which prevents the development of thrombosis and is used in primary and secondary prevention of cardiovascular and cardioembolic events (eg. CE MU). Increased risk of these disorders is brought into connection with genetic resistance to clopidogrel as a result of the presence of at least one variant allele CYP2C19 *2 / *3