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.

Occurrence and Risk of Cochleotoxicity in Cystic Fibrosis Patients Receiving Repeated High-Dose Aminoglycoside Therapy

“…If the median number of courses taken by all CF subjects are used as an estimate for x then, from Table 1 While this single exponential estimate has some practical utility, it is probably suboptimal. Experimental work (2,12,15,19,43) strongly suggests that AGs accumulate in cochlear sensory cells. Consequently, a better estimate would be provided by an equation including additional terms that models a cumulative component of risk.…”

“…2 suggest an idiosyncratic response to repeated AG exposure. This absence of a linear relationship is likely to reflect the multifactorial contribution to the onset and progression of AG-induced hearing loss (2,4,12,15,18,19,28,43). This idea is supported by a number of distinct pharmacokinetic and biochemical processes identified from experimentally induced cochleotoxicity outlined below.…”

“…Within the OHCs and IHCs, the main features determining cochleotoxicity are (i) an AG "storage" threshold, below which AG remains as a dormant "protoxin" and, when this threshold is exceeded, AG is involved in the generation of an "active toxin" species (2,12,15,19,43) and (ii) detoxicant processes involving free-radical scavengers that may ameliorate the severity of damage. This suggests that the active toxin is a freeradical species (37,38).…”

Antioxidant Enzyme Levels Inversely Covary with Hearing Loss After Amikacin Treatment

“…Sha and Schacht (1999) found that a cytotoxic metabolite produced after initial exposure to AG generates free radicals in a chain reaction. Crann and Schacht (1996) found thatAGs form a secondary toxic compound within the cochlea itself. The combined effects of prolonged AG retention in the cochlea and cochlear conversion of AGs into a toxic metabolite contribute to the delayed component of AG-induced hearing loss.…”

A direct HPLC method to estimate streptomycin and its putative ototoxic derivative, streptidine, in blood serum: Application to streptomycin-treated humans

“…Thus, some investigators have postulated a metabolic transformation or activation to produce a molecular species derived from the antibiotic which may show greater toxicity than the drug itself, or alternatively these derivatives may act in combination with the antibiotic, producing the ototoxic effect [1]. Studies with kanamycin [2], gentamicin [3,4] and streptomycin (STP) [5] have been performed, but the resulting metabolites have not been identified and characterized.…”