Multidrug Resistance-Associated Protein 3 Plays an Important Role in Protection against Acute Toxicity of Diclofenac.
نویسندگان
چکیده
Diclofenac (DCF) is a nonsteroidal anti-inflammatory drug commonly prescribed to reduce pain in acute and chronic inflammatory diseases. One of the main DCF metabolites is a reactive diclofenac acyl glucuronide (DCF-AG) that covalently binds to biologic targets and may contribute to adverse drug reactions arising from DCF use. Cellular efflux of DCF-AG is partially mediated by multidrug resistance-associated proteins (Mrp). The importance of Mrp2 during DCF-induced toxicity has been established, yet the role of Mrp3 remains largely unexplored. In the present work, Mrp3-null (KO) mice were used to study the toxicokinetics and toxicodynamics of DCF and its metabolites. DCF-AG plasma concentrations were 90% lower in KO mice than in wild-type (WT) mice, indicating that Mrp3 mediates DCF-AG basolateral efflux. In contrast, there were no differences in DCF-AG biliary excretion between WT and KO, suggesting that only DCF-AG basolateral efflux is compromised by Mrp3 deletion. Susceptibility to toxicity was also evaluated after a single high DCF dose. No signs of injury were detected in livers and kidneys; however, ulcers were found in the small intestines. Furthermore, the observed intestinal injuries were consistently more severe in KO compared with WT. DCF covalent adducts were observed in liver and small intestines; however, staining intensity did not correlate with the severity of injuries, implying that tissues respond differently to covalent modification. Overall, the data provide strong evidence that (1) in vivo Mrp3 plays an important role in DCF-AG disposition and (2) compromised Mrp3 function can enhance injury in the gastrointestinal tract after DCF treatment.
منابع مشابه
Multidrug Resistence-associated Protein 3 (mrp3) Plays an Important Role in Protection against Acute Toxicity of Diclofenac
متن کامل
Hepatic clearance of reactive glucuronide metabolites of diclofenac in the mouse is dependent on multiple ATP-binding cassette efflux transporters.
Diclofenac is an important analgesic and anti-inflammatory drug that is widely used for the treatment of postoperative pain, rheumatoid arthritis, and chronic pain associated with cancer. Diclofenac is extensively metabolized in the liver, and the main metabolites are hydroxylated and/or glucuronidated conjugates. We show here that loss of multidrug resistance protein 2 (MRP2/ABCC2) and breast ...
متن کاملEffects of Salinispora derived metabolites against multidrug resistance, an in-silico study
Background: Multidrug resistance (MDR) is known to defeat most chemotherapies as one of the main anticancer strategies. The role of overexpression/overactivation of ABC transporters, especially P-glycoprotein (P-gp), in the development of chemotherapy has long been demonstrated. Salinispora is a marine actinomycete genus known for the production of novel bioactive metabolites. Methods: In this...
متن کاملDifferential protein expression in Mycobacterium tuberculosis susceptible and multidrug resistant isolates
Introduction: Infections by multidrug resistant Mycobacterium tuberculosis (MDR-TB) is a major public health challenge. Secretion of proteins by M. tuberculosis plays an important role in the pathogenesis of the bacterium. We compared the protein profiles of susceptible M. tuberculosis and MDR-TB isolates using proteomic analyses, namely two dimensional gel electrophoresis (2DE) and mass spectr...
متن کاملThe role of ATP-binding cassette transporter A2 in childhood acute lymphoblastic leukemia multidrug resistance
Acute lymphoblastic leukemia (ALL) is one of the most prevalent hematologic malignancies in children. Although the cure rate of ALL has improved over the past decades, the most important reason for ALL treatment failure is multidrug resistance (MDR) phenomenon. The current study aims to explain the mechanisms involved in multidrug resistance of childhood ALL, and introduces ATP-binding cassette...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید
ثبت ناماگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید
ورودعنوان ژورنال:
- Drug metabolism and disposition: the biological fate of chemicals
دوره 43 7 شماره
صفحات -
تاریخ انتشار 2015