Interaction of metronidazole with nucleic acids in vitro

Nicholas F La Russo, M. Tomasz, M. Muller, R. Lipman

Research output: Contribution to journalArticle

94 Citations (Scopus)

Abstract

The binding of metronidazole [1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole] to nucleic acids was quantitated and characterized in vitro. [14C]Metronidazole was incubated with nucleic acid under various conditions, the nucleic acid and associated 14C were separated from lower molecular weight compounds by molecular sieve chromatography, and nucleic acid concentration and radioactivity were measured in the eluate. Maximum binding occurred when metronidazole was reduced by sodium dithionite in the presence of calf thymus DNA (0.73 molecule of drug per 103 nucleotides). Binding was significantly less if metronidazole was reduced prior to incubation with DNA, and did not occur with unreduced metronidazole. Binding of reductively activated metronidazole to bacterial and phage DNA and yeast tRNA was also demonstrated; it was 2 times greater to alkali-denatured than to native DNA, was less in the presence of MgCl2 or NaH2PO4 and at higher pH, and did not affect the melting temperature or renaturation profile of calf thymus DNA. While 15-30% of bound 14C was released by dialysis or rechromatography, the majority of the label remained complexed to nucleic acid under a variety of conditions known to dissociate noncovalent complexes. Studies with synthetic polynucleotides suggested binding specificity of reductively activated metronidazole for guanine and cytosine. Both unreduced and dithionite-reduced metronidazole bound to bovine serum albumin, and binding of the reduced drug was approximately 35% of binding to nucleic acids. The results indicate that reduction of metronidazole in vitro yields a short-lived, activated compound(s) which, while not cross-linking, binds largely in a covalent fashion primarily to guanine and cytosine of mammalian, bacterial and phage DNA. This binding may have implications for the antimicrobial, mutagenic, and radiosensitizing actions of this drug.

Original languageEnglish (US)
Pages (from-to)872-882
Number of pages11
JournalMolecular Pharmacology
Volume13
Issue number5
StatePublished - 1977
Externally publishedYes

Fingerprint

Metronidazole
Nucleic Acids
Dithionite
Bacterial DNA
Cytosine
Guanine
Bacteriophages
Radiation-Sensitizing Agents
In Vitro Techniques
Polynucleotides
Magnesium Chloride
DNA
Alkalies
Bovine Serum Albumin
Transfer RNA
Pharmaceutical Preparations
Radioactivity
Freezing
Gel Chromatography
Dialysis

ASJC Scopus subject areas

  • Pharmacology

Cite this

La Russo, N. F., Tomasz, M., Muller, M., & Lipman, R. (1977). Interaction of metronidazole with nucleic acids in vitro. Molecular Pharmacology, 13(5), 872-882.

Interaction of metronidazole with nucleic acids in vitro. / La Russo, Nicholas F; Tomasz, M.; Muller, M.; Lipman, R.

In: Molecular Pharmacology, Vol. 13, No. 5, 1977, p. 872-882.

Research output: Contribution to journalArticle

La Russo, NF, Tomasz, M, Muller, M & Lipman, R 1977, 'Interaction of metronidazole with nucleic acids in vitro', Molecular Pharmacology, vol. 13, no. 5, pp. 872-882.
La Russo, Nicholas F ; Tomasz, M. ; Muller, M. ; Lipman, R. / Interaction of metronidazole with nucleic acids in vitro. In: Molecular Pharmacology. 1977 ; Vol. 13, No. 5. pp. 872-882.
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