Genotoxicity Of Ciprofloxacin In Mammalian Test System
Lopamudra Das Roy*, Sarbani Giri**
Molecular Cytogenetics Laboratory, Deptt. of Life Science Assam University, Silchar-788011 *, Molecular Cytogenetics Laboratory, Deptt. of Life Science Assam University, Silchar-788011 **
Introduction
Ciprofloxacin (CIP) is a broad-spectrum antibiotic that is active against both Gram-positive and Gram-negative bacteria. It functions by inhibiting DNA gyrase, a type II topoisomerase, which is an enzyme necessary to separate replicated DNA, thereby inhibiting cell division. CIP belongs to a group called fluoroquinolones. Genotoxicity data on Ciprofloxacin in mammalian test system are contradictory. Further there is insufficient data about its effects on Sperm Morphology.
Objectives
In our study, the genotoxic potential of CIP was evaluated in Swiss albino mice in vivo using chromosome aberration (CA), micronucleus (MN) and sperm head abnormality (SA) assays. The interaction between low dose of radiation on CIP as well as the effect of Vitamin C on CIP induced genotoxicity was also evaluated.

Methodology: CIP used was of pharmaceutical grade. Swiss albino mice in the age group of 10-12 weeks were used as test animals. CA, MN and SA assays were carried out using standard protocols. The bone marrow cells were fixed at 24 hrs after the treatments for CA and MN assays. For sperm shape abnormality assay, the animals were sacrificed after 24 h and 21 days of treatment. Three acute doses (10 mg/kg, 30 mg/kg and 50 mg/kg bw) and one chronic dose (3x16.7) mg/kg bw) administered intraperitoneally (i.p.) were tested for occurrence of CA, MN and SA. The highest acute dose (50 mg/kg) used in our study was selected on the basis of human equivalent dose. In the Vitamin C intervention study, the dose of Vitamin C used was 500 mg/kg bw per day. The Vitamin C was given orally by gavage (p.o.) for 5 consecutive days prior to the treatment with highest acute and chronic dose of CIP. The Cobalt-60 irradiation dose was fixed at 0.5 Gy. The radiation exposure was given either 30 minutes prior or following CIP treatment. Mitomycin-C (MMC) (2 mg/kg) was used as a positive control and the untreated control were given equal volume of isotonic saline (0.89% NaCI) only.
Results
Acute highest and chronic dose showed higher incidence of CA after 24 hrs of treatment when compared to the untreated control (P<0.001). In the combination studies with Vitamin C, decrease in the frequency of chromosome aberrations was observed though not statistically significant in the groups receiving the combined treatment as compared to the respective groups receiving CIP along. In the combination studies with 0.5 Gy of radiation, it was observed that exposure to radiation prior or following CIP treatment induced significantly (P<0.001) higher frequency of chromosome aberration in the bone marrow cells as compared to the groups receiving CIP treatment alone. The incidence of MN was statistically high with the highest acute and chronic doses of CIP when compared to untreated control (P<0.01). In the Vitamin C and CIP combination treatment studies, as compared to the CIP alone, Vitamin C pre-treatment caused significant reduction in the frequency of total micronuclei in the bone marrow cells of mice at certain dose. In the combination studies with radiation, it was observed that CIP in combination with low doses of radiation induced significant increase in the frequency of micronuclei in the bone marrow cells of mice following 24 h of the treatment as compared to the respective groups receiving CIP alone. All the doses tested induced significantly (P<0.00 I) higher frequency of sperm head abnormality as compared to the control both at 24 h and 21 days of the treatment. In the combination studies with Vitamin C and CIP, significant level of sperm head abnormality persisted even after pretreatment with Vitamin C as compared to the respective control groups both at 24 h and 21days of the treatment. In the combination studies with radiation and CIP, both pre and post treatment resulted in marked increase in the frequency of sperm head abnormality at 24 hrs and 21 days of the treatment as compared to the groups receiving CIP alone.
Discussion
CIP is a poor inducer of CA and MN in acute low and middle dose. However in acute highest and chronic dose the incidence of CA and MN is quite high. The present findings support the clastogenic potential of CIP. The significant increase in the sperm head abnormality observed could be due to interference of CIP in the differentiation process of the sperm or interaction with cell membrane components like membrane lipids thus resulting in distortion in the head morphology. In addition, CIP in combination with low dose radiation increased the potential mutagenic risk. However Vitamin C supplementation during the course of CIP treatment did not show a significant level of protection except for certain parameters. The present study indicates that CIP has a higher potential to cause genetic alterations in mouse test system and may also pose a mutagenic risk to human beings and hence frequent use should be avoided.
Acknowledgement

We are thankful to the Principal, Silchar Medical College to allow us to use the instrument for radiation. We are also thankful to the Radiology and Pathology Department, SMC for their support and help. We are thankful to the Head of the Department of Life Science, Assam University, Silchar for providing laboratory facilities.

*Present address: Cellular Immunology Laboratory, Mayo Clinic School of Medicine, Scottsdale, AZ 85259, United States.
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