Inhibition of renal ornithine decarboxylase by aminoglycoside antibiotics in vitro

• Published in: Biochemical pharmacology Vol. 37; no. 9; p. 1679
• Main Authors: Henley, 3rd, C M, Mahran, L G, Schacht, J
• Format: Journal Article
• Language: English
• Published: England 01.05.1988
• Subjects: Aminoglycosides - pharmacology; Animals; Anti-Bacterial Agents - pharmacology; Kidney - enzymology; Kinetics; Neomycin - pharmacology; Ornithine Decarboxylase Inhibitors
• DOI: 10.1016/0006-2952(88)90427-3
• ISSN: 0006-2952

The inhibition of renal ornithine decarboxylase (ODC) by aminoglycoside antibiotics was characterized in the postmitochondrial fraction of a kidney homogenate from adult pigmented guinea pigs. Enzymatic activity was defined as the rate of decarboxylation of [14C]ornithine sensitive to a specific ODC inhibitor, alpha-difluoromethylornithine (DFMO). The Km for ornithine was 61 +/- 32 microM. There were two forms of the enzyme with respect to their affinity for pyridoxal phosphate (PLP): (I) Km = 2.1 +/- 1.8 microM; (II) Km = 36.2 +/- 12.7 microM. Putrescine, a known ODC inhibitor, acted competitively on the renal enzyme with Ki = 1.7 +/- 1.4 mM. Aminoglycoside antibiotics inhibited ODC by an uncompetitive mechanism with inhibitor constants of comparable magnitude: neomycin, Ki = 1.3 +/- 0.1 mM; gentamicin, Ki = 1.6 +/- 0.1 mM; kanamycin, Ki = 1.9 +/- 0.2 mM; and netilmicin, Ki = 1.7 +/- 0.2 mM. Neomycin inhibited both forms of the enzyme (low and high affinity for PLP) uncompetitively with similar inhibitor constants (1.5 +/- 0.3 and 1.8 +/- 0.4 mM respectively), suggesting a single mechanism of action. Inhibition of ODC suggests that aminoglycoside-polyamine interactions may be an important component of the sequence of biochemical events associated with aminoglycoside toxicity.