Vplivi zaviralcev dihidrofolat reduktaze in sulfametoksazola na delovanje z AMP-aktivirane protein kinaze v kulturah človeških in podganjih skeletnomišičnih celic

Šutar, Mateja (author), Pirkmajer, Sergej (mentor), Miš, Katarina (co-mentor)

Z AMP aktivirana protein kinaza (AMPK) je osrednji energijski senzor na ravni celice in organizma ter obetavna tarča v terapiji presnovnih motenj. Raziskave kažejo, da metotreksat, zaviralec dihidrofolat reduktaze, in sulfanilamid sulfasalazin lahko vplivata na aktivnost AMPK v skeletni mišici. Mehanizem delovanja je inhibicija encima ATIC (5-amino-4-imidazolkarboksamid ribonukleotid formiltransferaza/inozin monofosfat ciklohidrolaza). S tem se upočasni presnova ZMP, ki je fosforilirana oblika AICAR, farmakološkega aktivatorja AMPK. Tako se zmanjša prag za z AICAR spodbujeno AMPK aktivacijo. Posledično se v celici povečata privzem glukoze in lipidna oksidacija, kar zmanjša hiperglikemijo in inzulinsko rezistenco pri osebah s sladkorno boleznijo tipa 2. Namen naloge je bil proučiti, ali na delovanje AMPK v skeletni mišici poleg metotreksata in sulfasalazina vplivajo tudi nekateri drugi klinično uporabni zaviralci dihidrofolat reduktaze (trimetreksat in trimetoprim) oziroma sulfanilamidi, kot je sulfametoksazol, ki se uporablja skupaj s trimetoprimom.

• Language: Slovenian
• Keywords: trimetoprim, sulfametoksazol, trimetreksat, AMPK, sladkorna bolezen tipa 2
• Work type: Master's thesis/paper
• Organization: FFA - Faculty of Pharmacy
• Year: 2021
• PID: 20.500.12556/RUL-131732
• Publication date in RUL: 02.10.2021

Secondary language

• Language: English
• Title: Effects of dihydrofolate reductase inhibitors and sulfamethoxazole on AMP-activated protein kinase in cultured human and rat skeletal muscle cells

Abstract

AMP-activated protein kinase (AMPK) is a central energy sensor at the cellular and organismal level and a promising target in the therapy of metabolic disorders. Studies show that methotrexate, a dihydrofolate reductase inhibitor, and the sulphanilamide sulfasalazine can affect AMPK activity in skeletal muscle. The mechanism of action is inhibition of the ATIC (5-amino-4-imidazolecarboxamide ribonucleotide formyltransferase/IMP cyclohydrolase) enzyme, which suppresses the metabolism of ZMP, a phosphorylated (active) form of pharmacological AMPK activator AICAR. In this way, the threshold for AICAR-stimulated AMPK activation is decreased. Consequently, cellular glucose uptake and lipid oxidation are increased, thus reducing hyperglycaemia and insulin resistance in persons with type 2 diabetes. Our aim was to investigate whether, in addition to methotrexate and sulfasalazine, AMPK function in skeletal muscle is modulated by some other clinically useful inhibitors of dihydrofolate reductase (trimetrexate and trimethoprim) or by sulphanilamides, such as sulfamethoxazole, which is used in combination with trimethoprim.

• Keywords: trimethoprim, sulfamethoxazole, trimetrexate, AMPK, type 2 diabetes mellitus