title: Solution chemistry of copper(II)-gentamicin complexes: relevance to metal-related aminoglycoside toxicity.
abstract: The adverse effect to the inner ear of aminoglycosides, drugs widely administered for the treatment of serious infections, appears to result from the interaction of these drugs with Cu(II) or Fe(II)/Fe(III) ions. To understand more completely the metal-induced side effects of one such antibiotic, gentamicin, we studied copper(II) coordination to gentamicin C1a by potentiometry, UV-vis, CD, and EPR spectroscopies, and ESI mass spectrometry. Only monomeric complexes of the CuH(n)L stoichiometry, with n ranging from 3 to -2, were detected over the pH range of 4-12. CuH(3)L and CuH(2)L complexes exhibit the same coordination mode, binding copper(II) through the amino nitrogen atom and a deprotonated alcoholic oxygen atom of the garosamine ring. In the CuHL and CuL complexes a second amino nitrogen atom of the purpurosamine ring participates in central ion coordination. Finally, the additional axial binding of the deprotonated oxygen of the hydroxyl group of the 2-deoxystreptamine moiety occurs in the CuH(-)(1)L and CuH(-)(2)L complexes. Interactions of the Cu(II)-gentamicin-H(2)O(2) system at pH 7.4 with N,N-dimethyl-p-nitrosoaniline, arachidonic acid, and plasmid DNA confirmed that gentamicin complexes facilitate oxidative reactions leading to peroxidation of arachidonic acid and scission of double-stranded DNA mediated by copper-bound reactive oxygen species. However, the stability constants of Cu(II)-gentamicin complexes are inferior to the binding constants of copper(II) complexes with other components of human serum or cells. Computer simulations of copper(II) distribution in the human blood plasma showed that the concentration of gentamicin would have to be at impossible levels (100 M) before a significant fraction of Cu(II) ions would be bound to gentamicin. Further, once introduced into aqueous solution, histidine replaces gentamicin in Cu(II)-gentamicin complexes. Therefore, Cu(II)-gentamicin complexes might not exist under physiological conditions.
authors.affiliation: Kresge Hearing Research Institute, Department of Otolaryngology, University of Michigan, Ann Arbor 48109, USA.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Lesniak
authors.forename: Wesley R
authors.initials: WR
authors.lastname: Harris
authors.forename: Joslyn Yudenfreund
authors.initials: JY
authors.lastname: Kravitz
authors.forename: Jochen
authors.initials: J
authors.lastname: Schacht
authors.forename: Vincent L
authors.initials: VL
authors.lastname: Pecoraro
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000378:metabolism; D001774:Blood Chemical Analysis; D002851:Chromatography, High Pressure Liquid; D002942:Circular Dichroism; D003198:Computer Simulation; D003300:Copper / Q000737:chemistry* / Q000378:metabolism; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D064420:Drug-Related Side Effects and Adverse Reactions; D004578:Electron Spin Resonance Spectroscopy; D005839:Gentamicins / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007501:Iron / Q000737:chemistry / Q000378:metabolism; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D010084:Oxidation-Reduction
chemical_list: D000900:Anti-Bacterial Agents; D005839:Gentamicins; D008024:Ligands; C100093:gentamicin C; D003300:Copper; D004247:DNA; D007501:Iron