Endogenous oxidoreductase expression is induced by aminoglycosides.
Oxidoreductases such as glutaredoxin are a major class of enzymes that reversibly catalyze thiol-disulfide exchange reactions. Transfection experiments using geneticin (G418) selection to identify the specific protein S-thiolated substrates of glutaredoxin-1 (Grx-1) noted the curious phenomenon that nontransfected control cells treated with G418 had increased levels of Grx-1 expression. Varied concentrations of gentamicin, kanamycin, and hygromycin increased Grx-1 expression in a time- and dose-dependent fashion in human cultured retinal pigment epithelial cells. Reactive oxygen species formation after aminoglycoside exposure correlated directly to aminoglycoside treatment. Further indication that oxidation regulates Grx-1 expression was noted by the positive effect of phorbol 12-myristate 13-acetate, a known inducer of redox-sensitive AP-1 transcription factor. In agreement with this hypothesis was the finding that the physiologic reductant N-acetylcysteine decreased Grx-1 expression whereas tert-butyl hydroperoxide increased Grx-1 expression. Our data suggest that aminoglycosides increased Grx-1 expression in response to oxidative stress.
Cole Eye Institute, Cleveland Clinic Foundation, OH 44195, USA.
George
G
Hoppe
Yuh Cherng
YC
Chai
Jonathan
J
Sears
D000617:Aminoglycosides / Q000494:pharmacology*; D002460:Cell Line; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005839:Gentamicins / Q000494:pharmacology; D054477:Glutaredoxins; D006801:Humans; D006921:Hygromycin B / Q000494:pharmacology; D007612:Kanamycin / Q000494:pharmacology; D009355:Neomycin / Q000494:pharmacology; D010084:Oxidation-Reduction; D010088:Oxidoreductases / Q000096:biosynthesis; D010857:Pigment Epithelium of Eye / Q000187:drug effects* / Q000378:metabolism*; D014176:Protein Biosynthesis; D017382:Reactive Oxygen Species / Q000032:analysis / Q000378:metabolism
D000617:Aminoglycosides; D016895:Culture Media, Serum-Free; C516005:GLRX protein, human; D005839:Gentamicins; D054477:Glutaredoxins; D017382:Reactive Oxygen Species; D006921:Hygromycin B; D007612:Kanamycin; C010680:antibiotic G 418; D010088:Oxidoreductases; D009355:Neomycin