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Activation of aminoglycoside antibiotics to cytotoxins
Abstract:
We have previously postulated an enzymatic transformation of gentamicin (to a metabolite or an 'activated' molecule) as part of its ototoxic action. Here we test with eight aminoglycosides whether the proposed mechanism applies to these antibiotics as a group. Drugs were activated by incubation with a subcellular fraction from liver, and cytotoxicity was tested in a bioassay using isolated outer hair cells from guinea pig. None of the aminoglycosides compromised the viability of the cells when assayed directly, i.e. without a preceding activation. In contrast, all clinically ototoxic aminoglycosides tested were significantly cytotoxic following the incubation. Neamine, considered to be non-ototoxic, did not yield a cytotoxin. A subcellular fraction from cochlear lateral wall tissues also converted gentamicin to a cytotoxin. The results support the hypothesis that activation of aminoglycosides precedes their toxic actions and demonstrate that the capability for activation is not confined to liver.
Insights
Aminoglycoside antibiotics require enzymatic activation to become toxic, causing hearing damage. This activation process, previously linked to gentamicin, is now confirmed for other ototoxic aminoglycosides using liver and cochlear cell fractions.
Area of Science:
- Pharmacology
- Toxicology
- Ototoxicity
Background:
- Aminoglycoside antibiotics, like gentamicin, are known to cause ototoxicity.
- A proposed mechanism involves enzymatic transformation of the drug into an 'activated' molecule.
- This study investigates if this activation mechanism applies to a broader range of aminoglycosides.
Purpose of the Study:
- To determine if enzymatic activation precedes the ototoxic effects of various aminoglycosides.
- To test the hypothesis that aminoglycoside ototoxicity is a group phenomenon mediated by activation.
- To investigate the role of liver and cochlear tissues in this activation process.
Main Methods:
- Eight different aminoglycosides were incubated with subcellular fractions from liver tissue.
- Cytotoxicity of the incubated drugs was assessed using a bioassay with isolated guinea pig outer hair cells.
- Subcellular fractions from cochlear lateral wall tissues were also used to test gentamicin activation.
Main Results:
- Directly applied aminoglycosides showed no cytotoxicity.
- Following incubation with liver fractions, all clinically ototoxic aminoglycosides tested became significantly cytotoxic.
- Neamine, a non-ototoxic aminoglycoside, did not produce a cytotoxin after incubation.
- Gentamicin was also activated to a cytotoxin by cochlear lateral wall tissue fractions.
Conclusions:
- Enzymatic activation is a prerequisite for the ototoxicity of aminoglycoside antibiotics.
- The capability for aminoglycoside activation is not limited to the liver and occurs in cochlear tissues.
- This finding supports a unified mechanism of ototoxicity across clinically relevant ototoxic aminoglycosides.