کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
8553463 | 1562588 | 2018 | 27 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Effect of UGT2B7*2 and CYP2C8*4 polymorphisms on diclofenac metabolism
دانلود مقاله + سفارش ترجمه
دانلود مقاله ISI انگلیسی
رایگان برای ایرانیان
کلمات کلیدی
Acyl glucuronidesESINADPH quinone oxidoreductaseCyPNSAIDUGTGSTNQO1TOFHLMNADPH cytochrome P450 reductase - NADPH سیتوکروم P450 ردوکتازUDP-glucuronosyltransferase - UDP-گلوکورونوسیل ترانسفرازDrug-induced liver injury - آسیب کبدی ناشی از مواد مخدرHuman leukocyte antigen - آنتی ژن لوسکسی انسانHLA - آنتیژن گلبول سفید انسانیNon-steroidal antiinflammatory drug - داروهای ضد التهابی غیر استروئیدیDILI - دیلیDiclofenac - دیکلوفناکtime of flight - زمان پروازCytochrome P450 - سیتوکروم پی۴۵۰Bioactivation - فعال سازی بیولوژیکGenome-wide association study - مطالعه مرتبط با ژنومGWAS - مطالعهٔ همخوانی سراسر ژنومHuman Liver Microsomes - میکروسومهای کبدی انسانیGenetic polymorphism - پلیمورفیسم ژنتیکیglutathione S-transferase - گلوتاتیون S-ترانسفرازelectrospray ionization - یونیزاسیون الکترو اسپری
موضوعات مرتبط
علوم زیستی و بیوفناوری
علوم محیط زیست
بهداشت، سم شناسی و جهش زایی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
The use of diclofenac is associated with rare but severe drug-induced liver injury (DILI) in a very small number of patients. The factors which predispose susceptible patients to hepatotoxicity of diclofenac are still incompletely understood. Formation of protein-reactive metabolites by UDP-glucuronosyl transferases and cytochromes P450 is commonly considered to play an important role, as indicated by the detection of covalent protein adducts and antibodies in the serum of patients suffering from diclofenac-induced liver injury. Since no associations have been found with HLA-alleles, polymorphisms of genes encoding for proteins involved in the disposition of diclofenac may be important. Previous association studies showed that possession of the UGT2B7*2 and CYP2C8*4 alleles is more common in cases of diclofenac-induced DILI. In the present study, the metabolism of diclofenac by UGT2B7*2 and CYP2C8*4 was compared with their corresponding wild-type enzymes. Enzyme kinetic analysis revealed that recombinant UGT2B7*2 showed an almost 6-fold lower intrinsic clearance of diclofenac glucuronidation compared to UGT2B7*1. The mutant CYP2C8*4 showed approximately 35% reduced activity in the 4â²-hydroxylation of diclofenac acyl glucuronide. Therefore, a decreased hepatic exposure to diclofenac acyl glucuronide is expected in patients with the UGT2B7*2 genotype. The increased risk for hepatotoxicity, therefore, might be the result from a shift to oxidative bioactivation to cytotoxic quinoneimines.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Toxicology Letters - Volume 284, 1 March 2018, Pages 70-78
Journal: Toxicology Letters - Volume 284, 1 March 2018, Pages 70-78
نویسندگان
Katarzyna E. Lazarska, Stefan J. Dekker, Nico P.E. Vermeulen, Jan N.M. Commandeur,