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Biomedical subjects

D I Edwards

Publications and source records attributed to D I Edwards.

At least 55 records · Page 3Linked to original sources
PubMed1986

DNA damage induced by reductively activated nitroimidazoles--pH effects.

The effect of pH on E. coli DNA damage measured viscometrically and induced by electrolytically reduced metronidazole and misonidazole has been studied, together with the effect on the statistical average number of electrons required for reduction, measured by high-resolution coulometry, and nitrite production measured colorimetrically. In general, nitroimidazole-induced DNA damage is greatest at acid pH and decreased at alkaline pH, but whereas metronidazole exhibits a linear relationship between DNA damage and increased pH, misonidazole shows a plateau between pH 6 and 8. The electron requirements for complete reduction (n) vary with pH. For misonidazole n increases with an increase in pH both in the absence and presence of DNA with a shallow plateau between pH 6 and 8. In contrast, for metronidazole, n decreases with increased pH and exhibits breakpoints between pH 6 and 8. Nitrite (NO2-) production is linear with increased pH for misonidazole but for metronidazole (NO2-) production shows a sudden increase at 7.5 yielding ca. 35% on a molar basis. The results may reflect differences in the relative stability and reactivity of the nitro radical anion.

DNA, Bacterial↗
PubMed1986

Satranidazole: mechanism of action on DNA and structure-activity correlations.

Satranidazole (CG-10213-Go), a novel nitroimidazole possessing a C-N linkage at C2 of the imidazole ring has been examined, during reduction, for its ability to damage DNA. Physical damage to DNA was measured by viscometry, thermal denaturation and renaturation, and hydroxyapatite chromatography. Biologically relevant DNA damage was measured by a bacteriophage transfection assay. The drug produces extensive DNA damage characterized by helix destabilization and strand breakage. Its comparison with other 2- and 5-nitroimidazoles indicate it may be more active towards anaerobes than many 5-nitroimidazoles because its relatively high redox potential may make it more resistant to inactivation by oxygen.

Chromatography↗
PubMed1985

Electrolytic reduction of nitroheterocyclic drugs leads to biologically important damage in DNA.

The effect of electrolytic reduction of nitroimidazole drugs on biologically active DNA was studied. The results show that reduction of the drugs in the presence of DNA affects inactivation for both double-stranded (RF) and single-stranded phi X174 DNA. However, stable reduction products did not make a significant contribution to the lethal damage in DNA. This suggests that probably a short-lived intermediate of reduction of nitro-compounds is responsible for damage to DNA.

Bacteriophage phi X 174↗
PubMed1984

The mechanism of nitroimidazole damage to DNA: coulometric evidence.

A high resolution coulometric technique has been developed to measure the electron requirement for reduction of 12 nitroimidazoles, both in the presence and absence of DNA. The cytotoxic species is shown to be a light sensitive intermediate of drug reduction and a common mechanism of cytotoxicity proposed which involves electron transfer from DNA to the one-electron radical anion (R-NO2-).

DNA, Bacterial↗
PubMed1984

Photosensitive interaction of RSU 1069 with DNA.

RSU 1069 is a 2-nitroimidazole radiosensitizer with an aziridine-containing side chain. In light (360 nm) the absorbance maximum of the nitro group at 325 nm disappears, which is accompanied by expulsion of the nitro group as the nitrite ion. We suggest an intramolecular cyclization of the aziridine side chain and the C2 of the imidazole ring as a possible explanation. This photosensitive effect was used to determine separately the damage to DNA induced by the reduced nitro group and the alkylating property of the aziridine. The aziridine-induced DNA damage is maximized in the dark when the nitro group is either absent (electrolytically reduced prior to the addition of DNA) or non functional (unreduced). In the light, damage is reduced. Typical DNA damage includes helix disruption leading to single strand breaks and the release of thymidine. Alkaline filter elution studies show evidence only for strand breakage and none for cross-linking indicating the drug is capable of mono-functional alkylation only.

Aziridines↗
PubMed1983

Studies on the action of nitroimidazole drugs. The products of nitroimidazole reduction.

The electron requirements for the electrolytic reduction of misonidazole, metronidazole and 4(5)-nitroimidazole have been measured using high-resolution coulometry. Eleven of the labelled final reduction products of metronidazole (a 5-nitroimidazole) have been separated by high-performance liquid chromatography and identified. These appear to be formed without the prior generation of a stable intermediate. In contrast, the reduction products of misonidazole (a 2-nitroimidazole) show little similarity to those of metronidazole but are likely to be formed via the four-electron hydroxylamine derivative. None of the final reduction products show toxicity towards Clostridium bifermentans or Escherichia coli suggesting that the short-lived cytotoxic agent of nitroimidazoles is a reduction product formed by the addition of not more than three electrons.

Chemical Phenomena↗
PubMed1983

Molecular basis of chloramphenicol and thiamphenicol toxicity to DNA in vitro.

The action of thiamphenicol and reduced chloramphenicol on DNA has been investigated in vitro. Reduced chloramphenicol causes DNA damage which is dependent upon reduction of the nitro group and which is characterized by helix destabilization and strand breakage. Although the reduction process requires six electrons indicating formation of the amine in 100% yield the toxic agent is most probably a short-lived reduction intermediate. We propose the one-electron nitro radical anion rather than the nitroso derivative as the toxic agent responsible for DNA damage related to aplastic anaemia. In contrast, thiamphenicol produces no such effects on DNA.

Chloramphenicol↗
PubMed1981

Interaction of nitroimidazole drugs with DNA in vitro: structure-activity relationships.

An electrolytic reduction system has been developed to model the cytotoxic action of a range of nitroimidazole drugs against DNA hypoxic cells or anaerobic microorganisms. THe degree of damage induced by these drugs (measured as the release of [14C]-dT from DNA) and their relative rates of reduction have been correlated with their redox potentials. The results show that the correlation of drug-induced damage and electron affinity is related to the amount of drug reduced, and supports the hypothesis that at the molecular level the cytotoxic mechanism of reduced nitroimidazoles is identical in hypoxic mammalian cells, bacteria and protozoa.

Cell Survival↗
PubMed1980

Mechanisms of selective toxicity of metronidazole and other nitroimidazole drugs.

The selectively toxic effect of nitroimidazole drugs towards anaerobic bacteria and protozoa depends on a number of factors. The killing action of such drugs as metronidazole requires the reduction of the nitro group, a process which influences the rate of entry of the drug into the susceptible cell and which is determined by mechanisms involving ferredoxin-linked (or the equivalent) reactions in the cell. The reduced agent subsequently causes strand breakage of DNA, the extent of which depends on the A + T content of the DNA. Other effects of such drugs may include the possible inhibition of DNA repair mechanisms which exacerbate DNA damage, Inhibition of activity of nitroimidazoles may be caused by aminothiol radical scavengers and radioprotectors normally present in the cell or by the presence of other organisms in the environment (that is, the vagina) capable of inactivating the drugs.

Anaerobiosis↗