DNA damage induced by reductively activated nitroimidazoles--pH effects

Area of Science:

• Microbiology
• Biochemistry
• Medicinal Chemistry

Background:

• Nitroimidazoles like metronidazole and misonidazole are used as antibiotics and radiosensitizers.
• Their efficacy can be influenced by cellular microenvironment factors, including pH.
• Understanding pH-dependent effects is crucial for optimizing their therapeutic use.

Purpose of the Study:

• To investigate the impact of pH on DNA damage induced by metronidazole and misonidazole in E. coli.
• To analyze the effect of pH on the reduction process and nitrite production of these drugs.

Main Methods:

• DNA damage was assessed using viscometry.
• Electron requirements for drug reduction were measured by high-resolution coulometry.
• Nitrite production was quantified colorimetrically.

Main Results:

• Nitroimidazole-induced DNA damage was greatest at acidic pH and decreased at alkaline pH.
• Metronidazole showed a linear correlation between DNA damage and pH, while misonidazole exhibited a plateau.
• Differences in electron requirements and nitrite production were observed between the two drugs across varying pH levels.

Conclusions:

• The study highlights significant pH-dependent variations in the DNA-damaging activity and reduction mechanisms of metronidazole and misonidazole.
• Observed differences suggest distinct stabilities and reactivities of their nitro radical anions.
• These findings have implications for the application of nitroimidazoles in different biological contexts.