Behçet Hastalarinda Sitokrom P450 2c (Cyp2c9 ve Cyp2c19) ve P-Glikoprotein Genetik Polimorfizm ve Aktivitelerinin İncelenmesi

Abstract

Behcet’s disease (BD) is a vasculitis with a wide distribution, involving muscle, skeletal, neurologic and gastrointestinal systems. The etiopathogenesis of BD is not fully understood. In addition to genetic component, environmental factors also play a role in BD. CYPs are the largest group of enzymes responsible for drug metabolism. One of these enzymes, CYP2C9, metabolizes many clinically used drugs. CYP2C9 shows genetic polymorphism and the most important variants having functional importance are CYP2C9*2 and CYP2C9*3. The CYP2C19 plays a role in the metabolism of many drugs, like proton pump inhibitors and some antiepileptics. Up to now, there are 28 alleles defined for CYP2C19. Many of these cause the loss or decrease of the enzyme activity (*2,*3,*11,*13,…) however, CYP2C19*17 increases the metabolic capacity of the enzyme. For the assessment of activity of cytochrome P450 enzymes probe drugs are used such as losartan for CYP2C9 and lansoprazole for CYP2C19. P-glycoprotein (P-gp) is a member of ATP Binding Cassette (ABC) family, which is responsible for the passage of drugs through biologic membranes. Many drug molecules like antineoplastics, antiarrhythmics, antihypertensives drugs have the property of being P-gp substrate. P-gp affects the pharmacokinetics of these drugs. The variations in ABCB1 gene can change the absorption, tissue distribution and response to therapy of these drugs. In the past studies, the relation between autoimmune diseases and drugs, genetic polymorphisms of the enzymes responsible for the metabolism of xenobiotics have been investigated. However, there are few studies related with BD, in this respect. At this study CYP2C9*2, *3, CYP2C19*2, *3, *17, MDR1 C3435 and G2677T/A polymorphisms among 59 BD and healthy people were determined by PCR-RFLP method. Besides, urine losartan and E-3174 levels for CYP2C9 phenotype and plasma lansoprazole and 5‐hydroxy lansoprazole concentrations for CYP2C19 phenotype were analyzed by an HPLC method. When CYP2C9*2,*3, CYP2C19*2, *3 and *17 genotype and allel distribution were examined for BD and healthy volunteers, although there was no difference for CYP2C9 genotypes, it was observed that CYP2C19*1 allel frequency was higher and *17 allel frequency was lower in BD compared to the healthy volunteers (p values: 0,03 and 0,01, respectively). Additionaly, CYP2C19*17*17 genotype frequency was found as 1,7% in BD and 14,8% in healthy volunteers (p=0,01). As we could see after literature browsing, our study is the first study at which CYP2C19*17 variant were researched for all autoimmune diseases including BD. It was observed that losartan / E-3174 metabolic ratio for BD which were included to our study were increased as 0,5 fold and this increase was found as statistically significant (p≤0,001). Besides, lansoprazole/5-hydroxy lansoprazole metabolic ratio was 2.26 fold higher in BD group compared to that of healthy volunteers (p=0,001). Furthermore, when MDR1 C3435T and G2677T/A genetical polymorphisms were compared between BD and healthy volunteers, there was not observed any statistically significant difference (p>0,05). Additionally, it was observed that MDR C3435T and G2677T/A polymorphisms did not effect losartan and lansoprazole metabolic ratios at the CYP2C9*1*1 and CYP2C19*1*1 BD groups. As a result, the activities of CYP2C9 and CYP2C19 decreased and the frequency of CYP2C19*17*17 genotype was lower in BD compared to the healthy volunteers. The decrease in enzyme activity may be related with colchicine use of BD patients or due to increased inflammatory cytokines in autoimmun diseases including BD, which have been reported to decrease the expression of CYP enzymes. Additionally, decreased metabolism of reactive oxygen species due to reduced enzyme activity and genotype difference may have a contribution to the pathophysiology of BD.