Abstract
Selenoprotein biosynthesis relies on the co-translational insertion of selenocysteine in response to UGA codons. Aminoglycoside antibiotics interfere with ribosomal function and may cause codon misreading. We hypothesized that biosynthesis of the selenium (Se) transporter selenoprotein P (SELENOP) is particularly sensitive to antibiotics due to its ten in frame UGA codons. As liver regulates Se metabolism, we tested the aminoglycosides G418 and gentamicin in hepatoma cell lines (HepG2, Hep3B and Hepa1-6) and in experimental mice. In vitro, SELENOP levels increased strongly in response to G418, whereas expression of the glutathione peroxidases GPX1 and GPX2 was marginally affected. Se content of G418-induced SELENOP was dependent on Se availability, and was completely suppressed by G418 under Se-poor conditions. Selenocysteine residues were replaced mainly by cysteine, tryptophan and arginine in a codon-specific manner. Interestingly, in young healthy mice, antibiotic treatment failed to affect Selenop biosynthesis to a detectable degree. These findings suggest that the interfering activity of aminoglycosides on selenoprotein biosynthesis can be severe, but depend on the Se status, and other parameters likely including age and general health. Focused analyses with aminoglycoside-treated patients are needed next to evaluate a possible interference of selenoprotein biosynthesis by the antibiotics and elucidate potential side effects.
Highlights
Aminoglycoside (AG) antibiotics interact mainly with the small ribosomal subunit of prokaryotes, and to a lesser extent of eukaryotes, resulting in errors in amino acid insertion during protein biosynthesis[1]
selenoprotein P (SELENOP) secreted by G418-treated cells (10 or 50 μg/ml) was found in the medium in almost equal amounts as compared to that secreted by cells supplemented with selenite
Supplemental selenite increased the net biosynthesis of G418-induced SELENOP in a dose-dependent manner and increased the relative Se content per secreted SELENOP molecule gradually (Fig. 4D). These results indicate an additive effect of G418 and selenite on SELENOP biosynthesis, with selenite increasing the Se content of SELENOP, whereas G418 increased the fraction of Se-poor SELENOP variants
Summary
Aminoglycoside (AG) antibiotics interact mainly with the small ribosomal subunit of prokaryotes, and to a lesser extent of eukaryotes, resulting in errors in amino acid insertion during protein biosynthesis[1]. AG-induced stop codon read-through is explored as an adjuvant treatment option in specific inherited diseases, e.g., in the suppression of premature stop codon mutations in the CFTR or DMD gene in patients suffering from cystic fibrosis or Duchenne muscular dystrophy[6, 7]. This line of research receives increasing attention in recent years, as 10–12% of genetic diseases seem to result from in-frame nonsense mutations[8, 9]. The transcript harbors two separate SECIS-elements differing in their efficiency of UGA recoding[15]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
