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Full Research Article

Evaluation the Cytotoxicity of Moxifloxacin in vivo and its Effect on the Functions and Tissues of the Liver and Kidney of Albino Male Mice

F
Farah T.O. Al-Jumaili1
S
Saja A. Shareef1
N
Noorhan Sabih Al-Maliki1
R
Ruqaya Mohammed Al-Ezzy1
A
Ashwaq A. Radi2
A
Abdulqader Mohammed Rashid3
A
Ahmed Flayyih Hasan2,3,*
1College of Biotechnology, Al-Nahrain University, Baghdad, Iraq.
2Biotechnology Research Center, Al-Nahrain University, Baghdad, Iraq.
3Department of Medical Laboratory Techniques, College of Health and Medical Technology, Al-Farabi University, Baghdad, Iraq.

ABSTRACT

Background: Moxifloxacin (MXF) is a broad spectrum fluoroquinolone antibiotic effective for respiratory and urinary tract infections. There are concerns that it may be cytotoxic and/or have organ-selective effects.

Methods: In vitro, WRL 68 (human liver) and HDFn (neonatal dermal fibroblast) cells were grown under standard condition at 37°C in Biotechnology Research Center/Al Nahrain University laboratory as control culture dish to apply MXF with concentrations of 12.5-400 µg/mL for 24 h. In vivo A total of 18 albino male mice were assigned into three groups (n=6 each) as follows: The control (given distilled water), MXF 500 and MXF 750 mg/kg treated intraperitoneally for a period of 15 days. Cell viability, micronucleus formation, hepatorenal function tests and histopathological studies were performed.

Result: MXF was cytotoxic in vitro at dose-dependent manner. Viability in WRL 68 cells was reduced from 95.3±0.6% at 12.5 µg/mL to 60.1±0.6% at 400 µg/mL or cytotoxicity of the range of 5.3-39.3%. HDFn cells were the most resistant (viability, 98.0±0.4% to 81.8±0.8%; cytotoxicity, 2.1-19.6%). In vivo, MN frequency in bone marrow were also significantly elevated at 750 mg/kg MXF (0.035±0.005 Mn/cell) vs controls (0.019±0.002 Mn/cell), while with 500 mg/kg only a small not significant increase was observed (0.021±0.003 Mn/cell). Liver enzymes (AST, ALT and ALP) were dose-dependent being 70.6±2.4, 67.1±2.42 and 200.1±21.5 U/L at 750 mg/kg when compared to control stress animal (45.5±1.37, 40.3±3.12, 79.4±8.7 U/L). There were increased levels of urea (58.7±5.4 mg/dL and 43.1±1.4, respectively) with no significantly differences in creatinine content. These biochemical results were consistent with the histology findings: moderate hepatitis and focal necrosis of the liver in mice given 750 mg/kg/day, no remarkable change in kidney at 500 mg/kg/day and almost normal architecture at a dose also of 750 mg/kg/day.

INTRODUCTION

Antibiotics are broadly used in a variety of infections in adults, such as respiratory tract infection, skin infection and urinary tract infection (Pham et al., 2019). Moxifloxacin (MXF), frequently employed in the treatment of tuberculosis (Millanao et al., 2021). Also its antibacterial potential is due to the penetration into the bacterial cell and action on DNA gyrase and topoisomerases II/IV, which are key enzymes in DNA replication, transcription, repair or recombination (Hooper et al., 2016). MXF has a potent activity against respiratory tract infections, including those caused by multidrug-resistant pneumococcal isolates and other anaerobic bacteria such as M tuberculosis (Gillespie, 2016). MXF has shown cytotoxicity against colon, bladder cancer and leukaemia cell lines (Hind et al., 2008) due to inhibition of topoisomerase II activity in eukaryotic cells or tumour cells (Fabian et al., 2006). MXF was also found to have a weak inhibitory effect on topoisomerase II purified from humans but in combination with the VP-16, which targeted human topoisomerase II, it exhibited synergistic action (73% decrease in enzyme activity). In addition, decreased VP-16-induced release of pro-inflammatory cytokines (IL-8, IL-1b, TNF), in THP1 cells (Bromberg et al., 2003). programme, information concerning the in vivo cytotoxic effects on hepatic and renal function and tissue integrity is still lacking. In preclinical studies, moxifloxacin demonstrates safety profile similar to that of other fluoroquinolones, but there is lack of detailed examination in organs particularly at biochemical and histological level in mammals (Nibell et al., 2022). Clinical and epidemiological data have revealed that exposure to fluoroquinolones can be linked with a risk of hepatotoxicity and drug induced liver injury (DILI), although the incidence, severity of hepatic adverse events differ among various agents and populations.Several experimental in vivo studies have also shown that treatment of mice with moxifloxacin can cause a dose dependent liver damage based on increase in biomarkers and morphological changes, suggesting possible hepatotoxic effects under particular dosing regimens (Hu et al., 2022). These observations reflect the dearth of information on the histological, histochemical and functional studies of both liver and kidney with respect to moxifloxacin administration particularly in albino male mice which further stressed the need for such a study. Therefore, the current study was designed to explore In Vitro toxicity of moxifloxacin and its effects on liver and kidney functions as well as tissue architecture, thus offering insights into the safety profile in non-cancerous tissues. The present study intended to investigate the cytotoxic activity of MXF on normal human cell lines as well as its impact on liver and kidney functions in albino male mice.

MATERIALS AND METHODS

In Vitro Cytotoxic potential of moxifloxacin on normal cell lines assay using (MTT) assay
 
Cytotoxicity of moxifloxacin (MXF) on normal human cell lines, WRL-68 (human normal liver cells) and HDFn (human dermal fibroblasts, neonatal); was evaluated. WRL-68 cells were grown in EMEM with 10% fetal bovine serum (FBS) while HDFn cells were cultured in fibroblast growth medium containing 10% FBS. All cultures were grown at 37°C in a humidified environment with 5% CO2. Cells were plated at a final volume of 100 µL/well in 96-well plates at a density of 1 × 104  cells/well and let them attach overnight. Moxifloxacin was dissolvedin sterile distilled water to obtain a stock drug solution and then it was diluted with culture medium suitable for each experimentto the concentrations of 12.5, 25, 50, 100, 200 and 400 µg/mL. Cells were incubated with different concentrations for 24 h at 37°C and 5% CO2. After treatments, the cell culture medium was withdrawn and 20 µL/well of MTT (5 mg/mL in PBS) solution was added. The plates were then incubated at 37°C for 4 h for formazan crystal formation. The culture medium containing MTT was aspirated and 40 μL of dimethyl sulfoxide (DMSO) were added to dissolve the formazan crystals in each well. After that, the plates were shaken and incubated for 15 minutes at 37°C. A microplate reader was used to detect optical density (OD) at 570 nm. The following formula was used to express cell survival as a percentage of untreated controls (Al-Taeea et al., 2026).


All experiments were conducted in triplicate and data were presented as the means±SD.
 
In Vivo evaluation of moxifloxacin activity hepatic, renal functional and histopathological changes
 
Albino male laboratory mice (Mus musculus) were utilized in the work. Animals Male Wistar mice were bought from the Biotechnology Research Center, Al-Nahrain University. Mice were 8-10 weeks old (23-27 g).
 
Experimental design
 
The mice were randomly separated into three testing groups with six mice per group (n=18 in total):
• Group I (Control): Mice were given distilled water only.
• Group II: Moxifloxacin was administered at 500 mg/kg body weight to mice.
• Group III: Moxifloxacin at 750 mg/kg was administered to mice.
       
Moxifloxacin was injected intraperitoneally (IP) (0.1 mL per mouse) at a single daily dose for 15 days throughout the study period. Mice were sacrified labratory on day 16 for serological/histopathological evaluation.
 
Serological analysis
 
After mice sacrified, blood samples were collected and serum was separated by centrifugation for biochemical estimations. Liver function was determined by the activities of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP); kidney function was assessed by determining the levels of serum urea and creatinine. All the biochemical parameters were spectrophotometrically determined by commercially available kits (Biolabo, France) on an automatic chemistry analyser BK-200 (Biobase, China), as per manufacturers’ instructions (Alankooshi et al., 2023; Hasan et al., 2021). 
 
Histological analysis
 
Liver and kidney tissue histology were performed, livers and kidneys were fixed in 10% formalin. The tissues were fixed, embedded in paraffin, cut into 6 µm sections using a microtome wheel rotation and stained with hematoxyline/eosine (H and E) for histopatology examination (Saleh et al., 2024; Alyasiri et al., 2025; Abd El-Rahmana et al., 2024). The slides were observed under a light microscope Optica, Italy and photographed.
 
Bone marrow micronucleus assay
 
Another parameters was micronucleus was estimated. The animals were sacrified at the end of the experimental period (day 16) and both femurs removed. Bone marrow was washed with fetal bovine serum and centrifuged smears were made on clean glass slides. The smears were air-dried, methanol fixed absolute and stained with Giemsa. Slides were visualized using a light microscope at 1000× magnification. At least 1000 bone marrow cells were scored per animal for determining the frequency of micronuclei and these data are presented as number of micronucleus per cell (Mn/cell) (Jain and Pandey, 2019; Al-Ameri et al., 2026).
 
Statistical analysis
 
Data was analysed statistically using SPSS and Minitab software and further data processing was done with the help of Microsoft Excel. Data are presented as mean±SD.

RESULTS AND DISCUSSION

Cytotoxic Effect of Moxifloxacin on Normal Cell Lines (WRL-68 and HDFn),The effect of moxifloxacin (MXF) on cell viability of WRL-68 (human normal liver cells) and HDFn (human dermal fibroblasts, neonatal) is presented in (Table 1, 2) and (Fig 1,2). In WRL-68 cells, MXF caused a concentration-dependent decrease in cell viability, with the highest concentration (400 µg/mL) reducing viability to 60.07±0.60%, while the lowest concentration (12.5 µg/mL) maintained 95.29±0.64% viability (Table 1). Correspondingly, cytotoxicity increased from 5.3% at 12.5 µg/mL to 39.3% at 400 µg/mL (Fig 1).

Table 1: Effect of MXF on WRL-68 cell viability.



Table 2: Effect of MXF on HDFn cell viability.



Fig 1: Cytotoxicity effect of moxifloxacin on the normal liver cell line (WRL-68).



Fig 2: Cytotoxicity effect of moxifloxacin on HDFn.


       
In HDFn cells, a similar concentration-dependent effect was observed, though overall cytotoxicity was lower. Cell viability decreased from 97.98±0.42% at 12.5 µg/mL to 81.82±0.77% at 400 µg/mL, corresponding to cytotoxicity values of 2.1% and 19.6%, respectively (Table 2, Fig 2). These results indicate that WRL-68 cells are more sensitive to MXF-induced cytotoxicity than HDFn cells.
 
Effect of MXF on micronucleus formation in mice bone marrow
 
Micronucleus formation in bone marrow cells of treated mice is presented in Table 3. A significant increase in micronucleus frequency was observed in the group treated with 750 mg/kg MXF (0.035±0.005 Mn/cell) compared to the control group (0.019±0.002 Mn/cell). At 500 mg/kg group showed a slight, non-significant increase (0.021±0.003 Mn/cell). These results indicate that high-dose MXF induces genotoxic effects in mouse bone marrow.

Fig 3: Liver of control showed normal appearance of central vein (C) and hepatocytes (asterisks). H and E stain.400x.


 
Effect of MXF on liver function
 
The effect of MXF on liver enzyme activities is summarized in Table 4. AST levels increased significantly in mice treated with 500 mg/kg (61.5±3.8 U/L) and 750 mg/kg (70.6±2.4 U/L) compared to control (45.5±1.37 U/L, P<0.05). ALT activity also increased to 55±5.66 U/L and 67.1±2.42 U/L for 500 and 750 mg/kg, respectively, versus 40.3±3.12 U/L in controls. Similarly, ALP levels were significantly elevated in treated groups, reaching 149.8±14.5 U/L (500 mg/kg) and 200.1±21.5 U/L (750 mg/kg) compared to 79.4±8.7 U/L in controls.

Table 4: Effect of MXF on liver function enzymes.


 
Effect of MXF on kidney function
 
Renal function results are presented in Table 5. Urea levels were significantly elevated in the 750 mg/kg group (58.73±5.42 mg/dL) compared to control (43.05±1.4 mg/dL, P≤0.05). Creatinine levels were slightly increased in treated groups but did not reach statistical significance.

Table 5: Effect of MXF on kidney function.


 
Histological study
 
Histological examination of control liver showed normal appearance of central vein and normal hepatocytes (asterisks) (Fig 3). On the other hand, Liver of 750 mg/kg MXF mice group showed moderate hepatitis characterized by multiple focal necrosis with mild sinusoidal infiltration mononuclear leukocytes (Fig 4), (Fig 5). Section of renal cortex (control) showed normal glomerular tuft, proximal and distal convoluted tubules with normal collecting tubules (Fig 6). 500 mg/kg MXF mice group showed mild sinusoidal infiltration of lymphocytes, monocytes, with mild focal (Fig 7). Renal cortex of third group (G3 750 mg/ml) showed normal glomerular tuft, proximal and distal convoluted tubules with collecting tubules (Fig 8).

Fig 3: Liver of control showed normal appearance of central vein (C) and hepatocytes (asterisks). H and E stain.400x.



Fig 4: Section of liver (G2 500) shows: Mild sinusoidal infiltration of lymphocytes (black arrows), monocytes (blue arrow), with mild focal necrosis (red arrow) and normal central vein (C). H and E stain.400x.



Fig 5: Section of liver (G3 750) shows: Moderate hepatitis characterized by multiple focal necrosis (Black arrow) with mild sinusoidal infiltration mononuclear leukocytes (Red arrow). H and E stain.100x.



Fig 6: Normal glomerular tuft (G), proximal and (P), distal convoluted tubules (D) and collecting tubules (C) are visible in the renal cortex (control) section. 400x H and E stain.



Fig 7: Section of kidney (G2 500) shows: Mild sinusoidal infiltration of lymphocytes (black arrows), monocytes (blue arrow), with mild focal necrosis (red arrow) and normal central vein (C). H and E stain.400x.



Fig 8: Normal glomerular tuft (G), proximal and (P), distal convoluted tubules (D) and collecting tubules (C) are displayed in the renal cortex section (G3 750 mg/ml). 400x H and E stain.


       
The present study showed that moxifloxacin (MXF) had a dose dependant cytotoxic impact on normal human cell lines, particularly the relative changes in WRL 68 (liver) cells were larger compared with those in HDFn (dermal fibroblasts). These results are consistent with our previous observations on the intrinsic cytotoxic effects of fluoroquinolone antibiotics (including moxifloxacin) against mammalian cells in vitro, which were dependent upon both concentration and exposure time (Al-Mashhadani et al., 2026). Also cytotoxicity implies that hepatocyte like cells may be more sensitive to oxidative stress and inhibition of cellular metabolism. It has been suggested that fluoroquinoloes generate reactive oxygen species (ROS) and produce oxidative damage in human cell cultures, which may contribute towards their cytotoxic properties demonstrated in our assays (Bhattacharya et al., 2020). Indeed, the role of oxidative stress as a potential mechanism in the cells treated with fluoroquinolones has been reported and it includes impairment in antioxidant defenses such reduced catalase activity or superoxide dis-mutase activity that may amplify cellular damage. The elevated mice micronucleus incidence in bone marrow cells at the highest MXF dose suggests a possible genotoxic activity in vivo. Although fluoroquinolones are thought mainly to target type II topoisomerases, studies suggest that they might also interact with DNA or disrupt DNA repair pathways in eukaryotic cells at high concentrations, leading to chromosomal aberrations and the formation of micronuclei (Hu et al., 2022; Rasheed et al., 2025). This genotoxic effect has been reported in other fluoroquinolone studies as well, in which ROS-mediated DNA damage was suggested to be involved in micronucleus induction (Hasan et al., 2024). For hepatic index, increases of the levels in activities of AST, ALT and ALP in MXF-treated mice indicate that hepatocellular injury associated with liver dysfunction. These biochemical modifications are corroborated by previous in vivo rodent studies whereby dose related hepatoxic responses were observed following moxifloxacin treatments, including serum liver markers and mouse histopathological changes. Clinical hepatotoxicity has also been reported for moxifloxacin with transient aminotransferase elevations and in rare instances acute liver injury, raising concerns of hepatic effects from high levels or chronic exposure, At the mechanism level, oxidative stress was suggested to be integral in moxifloxacin induced liver damage. Moxifloxacin can reduce the activities of hepatic antioxidant enzymes (catalase, glutathione S transferase) and lower endogenous antioxidants as indicated by a higher level of lipid peroxidation and ROS accumulation leading to greater hepatocyte damage (Khadra et al., 2012). Such redox disequilibrium might aggravate the biochemical indices of liver damage recorded in the current study. Renal profile demonstrated a marked rise of serum urea at higher dose levels of MXF, whereas creatinine ranged within non significant increase levels. A high urea has been described as an early biomarker of renal dysfunction, it can point out to impaired tubular reabsorption or enhanced protein catabolism under toxic challenge (Majalekar et al., 2020; Alyasiri et al., 2025). We have previously shown that even in animal models urea and creatinine are both increased after treatment with fluoroquinolones, highlighting renal sensitivity to oxidative and metabolic stress before overt histopathological damage occurs. Histologically, MXF produced mild hepatic inflammation and focal necrosis at the high dose, that is consistent with evidence of liver injury obtained biochemically. The mild lymphocytic infiltrate observed at 500 mg/kg in the kidney may signify subclinical renal response to exposure of MXF and the relatively well preserved histology in the kidney at higher dose shows early adaptive (or compensatory) histological changes before gross damage. These results are in agreement with previous studies investigating in rodents reversible or transient, dose dependent organ damage as shown longitudinally for liver often observed following termination of exposure.

CONCLUSION

The current studies showed that supra-inductly MXF is cytotoxic in tested normal human cell lines, genotoxic in mouse bone marrow and has hepatotoxicity as observed by increasing liver enzymes levels concomitant with pathological changes. Renal effects were slight, tangible as elevated urea levels and slight histological alterations. These responses underscore the overall safety of MXF at therapeutic doses, yet caution should be exercised when high or chronic exposures are anticipated and that close management of dose is advisable in order to reduce possible toxic effects.

LIMITATIONS

The study sample was small and the exposure duration (15 days) would be short to observe accumulation of arsenic in their organization. The authors did not examine mechanistic insights (including oxidative stress mechanisms) or apoptosis pathways. Large prospective studies of long-exposed individuals who have underwent molecular investigations were warranted in the future.
 
Ethical approval
 
The guidelines for care and use of laboratory animals were followed throughout all the experimental procedures, which were approved by the Scientific and Ethical Committee in Al-Nahrain University (Al-Nahrain ethical cpmmitte). Every attempt was made to limit the animals suffering and number of animals used.
 
Funding
 
None.

CONFLICT OF INTEREST

The writers guarantee that they have no competing interests.

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    Full Research Article

    Evaluation the Cytotoxicity of Moxifloxacin in vivo and its Effect on the Functions and Tissues of the Liver and Kidney of Albino Male Mice

    F
    Farah T.O. Al-Jumaili1
    S
    Saja A. Shareef1
    N
    Noorhan Sabih Al-Maliki1
    R
    Ruqaya Mohammed Al-Ezzy1
    A
    Ashwaq A. Radi2
    A
    Abdulqader Mohammed Rashid3
    A
    Ahmed Flayyih Hasan2,3,*
    1College of Biotechnology, Al-Nahrain University, Baghdad, Iraq.
    2Biotechnology Research Center, Al-Nahrain University, Baghdad, Iraq.
    3Department of Medical Laboratory Techniques, College of Health and Medical Technology, Al-Farabi University, Baghdad, Iraq.

    ABSTRACT

    Background: Moxifloxacin (MXF) is a broad spectrum fluoroquinolone antibiotic effective for respiratory and urinary tract infections. There are concerns that it may be cytotoxic and/or have organ-selective effects.

    Methods: In vitro, WRL 68 (human liver) and HDFn (neonatal dermal fibroblast) cells were grown under standard condition at 37°C in Biotechnology Research Center/Al Nahrain University laboratory as control culture dish to apply MXF with concentrations of 12.5-400 µg/mL for 24 h. In vivo A total of 18 albino male mice were assigned into three groups (n=6 each) as follows: The control (given distilled water), MXF 500 and MXF 750 mg/kg treated intraperitoneally for a period of 15 days. Cell viability, micronucleus formation, hepatorenal function tests and histopathological studies were performed.

    Result: MXF was cytotoxic in vitro at dose-dependent manner. Viability in WRL 68 cells was reduced from 95.3±0.6% at 12.5 µg/mL to 60.1±0.6% at 400 µg/mL or cytotoxicity of the range of 5.3-39.3%. HDFn cells were the most resistant (viability, 98.0±0.4% to 81.8±0.8%; cytotoxicity, 2.1-19.6%). In vivo, MN frequency in bone marrow were also significantly elevated at 750 mg/kg MXF (0.035±0.005 Mn/cell) vs controls (0.019±0.002 Mn/cell), while with 500 mg/kg only a small not significant increase was observed (0.021±0.003 Mn/cell). Liver enzymes (AST, ALT and ALP) were dose-dependent being 70.6±2.4, 67.1±2.42 and 200.1±21.5 U/L at 750 mg/kg when compared to control stress animal (45.5±1.37, 40.3±3.12, 79.4±8.7 U/L). There were increased levels of urea (58.7±5.4 mg/dL and 43.1±1.4, respectively) with no significantly differences in creatinine content. These biochemical results were consistent with the histology findings: moderate hepatitis and focal necrosis of the liver in mice given 750 mg/kg/day, no remarkable change in kidney at 500 mg/kg/day and almost normal architecture at a dose also of 750 mg/kg/day.

    INTRODUCTION

    Antibiotics are broadly used in a variety of infections in adults, such as respiratory tract infection, skin infection and urinary tract infection (Pham et al., 2019). Moxifloxacin (MXF), frequently employed in the treatment of tuberculosis (Millanao et al., 2021). Also its antibacterial potential is due to the penetration into the bacterial cell and action on DNA gyrase and topoisomerases II/IV, which are key enzymes in DNA replication, transcription, repair or recombination (Hooper et al., 2016). MXF has a potent activity against respiratory tract infections, including those caused by multidrug-resistant pneumococcal isolates and other anaerobic bacteria such as M tuberculosis (Gillespie, 2016). MXF has shown cytotoxicity against colon, bladder cancer and leukaemia cell lines (Hind et al., 2008) due to inhibition of topoisomerase II activity in eukaryotic cells or tumour cells (Fabian et al., 2006). MXF was also found to have a weak inhibitory effect on topoisomerase II purified from humans but in combination with the VP-16, which targeted human topoisomerase II, it exhibited synergistic action (73% decrease in enzyme activity). In addition, decreased VP-16-induced release of pro-inflammatory cytokines (IL-8, IL-1b, TNF), in THP1 cells (Bromberg et al., 2003). programme, information concerning the in vivo cytotoxic effects on hepatic and renal function and tissue integrity is still lacking. In preclinical studies, moxifloxacin demonstrates safety profile similar to that of other fluoroquinolones, but there is lack of detailed examination in organs particularly at biochemical and histological level in mammals (Nibell et al., 2022). Clinical and epidemiological data have revealed that exposure to fluoroquinolones can be linked with a risk of hepatotoxicity and drug induced liver injury (DILI), although the incidence, severity of hepatic adverse events differ among various agents and populations.Several experimental in vivo studies have also shown that treatment of mice with moxifloxacin can cause a dose dependent liver damage based on increase in biomarkers and morphological changes, suggesting possible hepatotoxic effects under particular dosing regimens (Hu et al., 2022). These observations reflect the dearth of information on the histological, histochemical and functional studies of both liver and kidney with respect to moxifloxacin administration particularly in albino male mice which further stressed the need for such a study. Therefore, the current study was designed to explore In Vitro toxicity of moxifloxacin and its effects on liver and kidney functions as well as tissue architecture, thus offering insights into the safety profile in non-cancerous tissues. The present study intended to investigate the cytotoxic activity of MXF on normal human cell lines as well as its impact on liver and kidney functions in albino male mice.

    MATERIALS AND METHODS

    In Vitro Cytotoxic potential of moxifloxacin on normal cell lines assay using (MTT) assay
     
    Cytotoxicity of moxifloxacin (MXF) on normal human cell lines, WRL-68 (human normal liver cells) and HDFn (human dermal fibroblasts, neonatal); was evaluated. WRL-68 cells were grown in EMEM with 10% fetal bovine serum (FBS) while HDFn cells were cultured in fibroblast growth medium containing 10% FBS. All cultures were grown at 37°C in a humidified environment with 5% CO2. Cells were plated at a final volume of 100 µL/well in 96-well plates at a density of 1 × 104  cells/well and let them attach overnight. Moxifloxacin was dissolvedin sterile distilled water to obtain a stock drug solution and then it was diluted with culture medium suitable for each experimentto the concentrations of 12.5, 25, 50, 100, 200 and 400 µg/mL. Cells were incubated with different concentrations for 24 h at 37°C and 5% CO2. After treatments, the cell culture medium was withdrawn and 20 µL/well of MTT (5 mg/mL in PBS) solution was added. The plates were then incubated at 37°C for 4 h for formazan crystal formation. The culture medium containing MTT was aspirated and 40 μL of dimethyl sulfoxide (DMSO) were added to dissolve the formazan crystals in each well. After that, the plates were shaken and incubated for 15 minutes at 37°C. A microplate reader was used to detect optical density (OD) at 570 nm. The following formula was used to express cell survival as a percentage of untreated controls (Al-Taeea et al., 2026).


    All experiments were conducted in triplicate and data were presented as the means±SD.
     
    In Vivo evaluation of moxifloxacin activity hepatic, renal functional and histopathological changes
     
    Albino male laboratory mice (Mus musculus) were utilized in the work. Animals Male Wistar mice were bought from the Biotechnology Research Center, Al-Nahrain University. Mice were 8-10 weeks old (23-27 g).
     
    Experimental design
     
    The mice were randomly separated into three testing groups with six mice per group (n=18 in total):
    • Group I (Control): Mice were given distilled water only.
    • Group II: Moxifloxacin was administered at 500 mg/kg body weight to mice.
    • Group III: Moxifloxacin at 750 mg/kg was administered to mice.
           
    Moxifloxacin was injected intraperitoneally (IP) (0.1 mL per mouse) at a single daily dose for 15 days throughout the study period. Mice were sacrified labratory on day 16 for serological/histopathological evaluation.
     
    Serological analysis
     
    After mice sacrified, blood samples were collected and serum was separated by centrifugation for biochemical estimations. Liver function was determined by the activities of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP); kidney function was assessed by determining the levels of serum urea and creatinine. All the biochemical parameters were spectrophotometrically determined by commercially available kits (Biolabo, France) on an automatic chemistry analyser BK-200 (Biobase, China), as per manufacturers’ instructions (Alankooshi et al., 2023; Hasan et al., 2021). 
     
    Histological analysis
     
    Liver and kidney tissue histology were performed, livers and kidneys were fixed in 10% formalin. The tissues were fixed, embedded in paraffin, cut into 6 µm sections using a microtome wheel rotation and stained with hematoxyline/eosine (H and E) for histopatology examination (Saleh et al., 2024; Alyasiri et al., 2025; Abd El-Rahmana et al., 2024). The slides were observed under a light microscope Optica, Italy and photographed.
     
    Bone marrow micronucleus assay
     
    Another parameters was micronucleus was estimated. The animals were sacrified at the end of the experimental period (day 16) and both femurs removed. Bone marrow was washed with fetal bovine serum and centrifuged smears were made on clean glass slides. The smears were air-dried, methanol fixed absolute and stained with Giemsa. Slides were visualized using a light microscope at 1000× magnification. At least 1000 bone marrow cells were scored per animal for determining the frequency of micronuclei and these data are presented as number of micronucleus per cell (Mn/cell) (Jain and Pandey, 2019; Al-Ameri et al., 2026).
     
    Statistical analysis
     
    Data was analysed statistically using SPSS and Minitab software and further data processing was done with the help of Microsoft Excel. Data are presented as mean±SD.

    RESULTS AND DISCUSSION

    Cytotoxic Effect of Moxifloxacin on Normal Cell Lines (WRL-68 and HDFn),The effect of moxifloxacin (MXF) on cell viability of WRL-68 (human normal liver cells) and HDFn (human dermal fibroblasts, neonatal) is presented in (Table 1, 2) and (Fig 1,2). In WRL-68 cells, MXF caused a concentration-dependent decrease in cell viability, with the highest concentration (400 µg/mL) reducing viability to 60.07±0.60%, while the lowest concentration (12.5 µg/mL) maintained 95.29±0.64% viability (Table 1). Correspondingly, cytotoxicity increased from 5.3% at 12.5 µg/mL to 39.3% at 400 µg/mL (Fig 1).

    Table 1: Effect of MXF on WRL-68 cell viability.



    Table 2: Effect of MXF on HDFn cell viability.



    Fig 1: Cytotoxicity effect of moxifloxacin on the normal liver cell line (WRL-68).



    Fig 2: Cytotoxicity effect of moxifloxacin on HDFn.


           
    In HDFn cells, a similar concentration-dependent effect was observed, though overall cytotoxicity was lower. Cell viability decreased from 97.98±0.42% at 12.5 µg/mL to 81.82±0.77% at 400 µg/mL, corresponding to cytotoxicity values of 2.1% and 19.6%, respectively (Table 2, Fig 2). These results indicate that WRL-68 cells are more sensitive to MXF-induced cytotoxicity than HDFn cells.
     
    Effect of MXF on micronucleus formation in mice bone marrow
     
    Micronucleus formation in bone marrow cells of treated mice is presented in Table 3. A significant increase in micronucleus frequency was observed in the group treated with 750 mg/kg MXF (0.035±0.005 Mn/cell) compared to the control group (0.019±0.002 Mn/cell). At 500 mg/kg group showed a slight, non-significant increase (0.021±0.003 Mn/cell). These results indicate that high-dose MXF induces genotoxic effects in mouse bone marrow.

    Fig 3: Liver of control showed normal appearance of central vein (C) and hepatocytes (asterisks). H and E stain.400x.


     
    Effect of MXF on liver function
     
    The effect of MXF on liver enzyme activities is summarized in Table 4. AST levels increased significantly in mice treated with 500 mg/kg (61.5±3.8 U/L) and 750 mg/kg (70.6±2.4 U/L) compared to control (45.5±1.37 U/L, P<0.05). ALT activity also increased to 55±5.66 U/L and 67.1±2.42 U/L for 500 and 750 mg/kg, respectively, versus 40.3±3.12 U/L in controls. Similarly, ALP levels were significantly elevated in treated groups, reaching 149.8±14.5 U/L (500 mg/kg) and 200.1±21.5 U/L (750 mg/kg) compared to 79.4±8.7 U/L in controls.

    Table 4: Effect of MXF on liver function enzymes.


     
    Effect of MXF on kidney function
     
    Renal function results are presented in Table 5. Urea levels were significantly elevated in the 750 mg/kg group (58.73±5.42 mg/dL) compared to control (43.05±1.4 mg/dL, P≤0.05). Creatinine levels were slightly increased in treated groups but did not reach statistical significance.

    Table 5: Effect of MXF on kidney function.


     
    Histological study
     
    Histological examination of control liver showed normal appearance of central vein and normal hepatocytes (asterisks) (Fig 3). On the other hand, Liver of 750 mg/kg MXF mice group showed moderate hepatitis characterized by multiple focal necrosis with mild sinusoidal infiltration mononuclear leukocytes (Fig 4), (Fig 5). Section of renal cortex (control) showed normal glomerular tuft, proximal and distal convoluted tubules with normal collecting tubules (Fig 6). 500 mg/kg MXF mice group showed mild sinusoidal infiltration of lymphocytes, monocytes, with mild focal (Fig 7). Renal cortex of third group (G3 750 mg/ml) showed normal glomerular tuft, proximal and distal convoluted tubules with collecting tubules (Fig 8).

    Fig 3: Liver of control showed normal appearance of central vein (C) and hepatocytes (asterisks). H and E stain.400x.



    Fig 4: Section of liver (G2 500) shows: Mild sinusoidal infiltration of lymphocytes (black arrows), monocytes (blue arrow), with mild focal necrosis (red arrow) and normal central vein (C). H and E stain.400x.



    Fig 5: Section of liver (G3 750) shows: Moderate hepatitis characterized by multiple focal necrosis (Black arrow) with mild sinusoidal infiltration mononuclear leukocytes (Red arrow). H and E stain.100x.



    Fig 6: Normal glomerular tuft (G), proximal and (P), distal convoluted tubules (D) and collecting tubules (C) are visible in the renal cortex (control) section. 400x H and E stain.



    Fig 7: Section of kidney (G2 500) shows: Mild sinusoidal infiltration of lymphocytes (black arrows), monocytes (blue arrow), with mild focal necrosis (red arrow) and normal central vein (C). H and E stain.400x.



    Fig 8: Normal glomerular tuft (G), proximal and (P), distal convoluted tubules (D) and collecting tubules (C) are displayed in the renal cortex section (G3 750 mg/ml). 400x H and E stain.


           
    The present study showed that moxifloxacin (MXF) had a dose dependant cytotoxic impact on normal human cell lines, particularly the relative changes in WRL 68 (liver) cells were larger compared with those in HDFn (dermal fibroblasts). These results are consistent with our previous observations on the intrinsic cytotoxic effects of fluoroquinolone antibiotics (including moxifloxacin) against mammalian cells in vitro, which were dependent upon both concentration and exposure time (Al-Mashhadani et al., 2026). Also cytotoxicity implies that hepatocyte like cells may be more sensitive to oxidative stress and inhibition of cellular metabolism. It has been suggested that fluoroquinoloes generate reactive oxygen species (ROS) and produce oxidative damage in human cell cultures, which may contribute towards their cytotoxic properties demonstrated in our assays (Bhattacharya et al., 2020). Indeed, the role of oxidative stress as a potential mechanism in the cells treated with fluoroquinolones has been reported and it includes impairment in antioxidant defenses such reduced catalase activity or superoxide dis-mutase activity that may amplify cellular damage. The elevated mice micronucleus incidence in bone marrow cells at the highest MXF dose suggests a possible genotoxic activity in vivo. Although fluoroquinolones are thought mainly to target type II topoisomerases, studies suggest that they might also interact with DNA or disrupt DNA repair pathways in eukaryotic cells at high concentrations, leading to chromosomal aberrations and the formation of micronuclei (Hu et al., 2022; Rasheed et al., 2025). This genotoxic effect has been reported in other fluoroquinolone studies as well, in which ROS-mediated DNA damage was suggested to be involved in micronucleus induction (Hasan et al., 2024). For hepatic index, increases of the levels in activities of AST, ALT and ALP in MXF-treated mice indicate that hepatocellular injury associated with liver dysfunction. These biochemical modifications are corroborated by previous in vivo rodent studies whereby dose related hepatoxic responses were observed following moxifloxacin treatments, including serum liver markers and mouse histopathological changes. Clinical hepatotoxicity has also been reported for moxifloxacin with transient aminotransferase elevations and in rare instances acute liver injury, raising concerns of hepatic effects from high levels or chronic exposure, At the mechanism level, oxidative stress was suggested to be integral in moxifloxacin induced liver damage. Moxifloxacin can reduce the activities of hepatic antioxidant enzymes (catalase, glutathione S transferase) and lower endogenous antioxidants as indicated by a higher level of lipid peroxidation and ROS accumulation leading to greater hepatocyte damage (Khadra et al., 2012). Such redox disequilibrium might aggravate the biochemical indices of liver damage recorded in the current study. Renal profile demonstrated a marked rise of serum urea at higher dose levels of MXF, whereas creatinine ranged within non significant increase levels. A high urea has been described as an early biomarker of renal dysfunction, it can point out to impaired tubular reabsorption or enhanced protein catabolism under toxic challenge (Majalekar et al., 2020; Alyasiri et al., 2025). We have previously shown that even in animal models urea and creatinine are both increased after treatment with fluoroquinolones, highlighting renal sensitivity to oxidative and metabolic stress before overt histopathological damage occurs. Histologically, MXF produced mild hepatic inflammation and focal necrosis at the high dose, that is consistent with evidence of liver injury obtained biochemically. The mild lymphocytic infiltrate observed at 500 mg/kg in the kidney may signify subclinical renal response to exposure of MXF and the relatively well preserved histology in the kidney at higher dose shows early adaptive (or compensatory) histological changes before gross damage. These results are in agreement with previous studies investigating in rodents reversible or transient, dose dependent organ damage as shown longitudinally for liver often observed following termination of exposure.

    CONCLUSION

    The current studies showed that supra-inductly MXF is cytotoxic in tested normal human cell lines, genotoxic in mouse bone marrow and has hepatotoxicity as observed by increasing liver enzymes levels concomitant with pathological changes. Renal effects were slight, tangible as elevated urea levels and slight histological alterations. These responses underscore the overall safety of MXF at therapeutic doses, yet caution should be exercised when high or chronic exposures are anticipated and that close management of dose is advisable in order to reduce possible toxic effects.

    LIMITATIONS

    The study sample was small and the exposure duration (15 days) would be short to observe accumulation of arsenic in their organization. The authors did not examine mechanistic insights (including oxidative stress mechanisms) or apoptosis pathways. Large prospective studies of long-exposed individuals who have underwent molecular investigations were warranted in the future.
     
    Ethical approval
     
    The guidelines for care and use of laboratory animals were followed throughout all the experimental procedures, which were approved by the Scientific and Ethical Committee in Al-Nahrain University (Al-Nahrain ethical cpmmitte). Every attempt was made to limit the animals suffering and number of animals used.
     
    Funding
     
    None.

    CONFLICT OF INTEREST

    The writers guarantee that they have no competing interests.

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