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Impact of Calotropis procera on potassium bromate-induced hepatotoxicity
* Corresponding author: E-mail address: jtamimi@ksu.edu.sa (J Al-Tamimi)
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Received: ,
Accepted: ,
Abstract
This study aims to investigate the impact of Calotropis procera extract (CPE) on liver damage resulting from potassium bromate. Twenty-five rats were assigned to five groups: a control group (CN), a PB group that received a single dose at 150 mg/kg body weight, a CPE group that received 2 mg/kg twice weekly for 1 month, and two combination groups (PB+CPE at 2 mg/kg and 4 mg/kg, respectively). Gas chromatography-mass spectrometry (GC-MS) analysis of the CPE was performed. GC-MS analysis indicated that CPE contains a mixture of compounds, with 1,3-cyclopentanedione, 4-(3-methylbutyl), and 2,3-bis (1-methylallyl) pyrrolidine being the most abundant. We evaluated various liver function markers, oxidative stress indices, and histopathological analysis of the hepatic tissues. Group PB rats exhibited a significant increase in alkaline phosphatase (ALP), alanine transaminase (ALT), aspartate transaminase (AST), gamma-glutamyl transferase (GGT), and total bilirubin levels as compared to the CN group. The CPE-treated group showed a similar pattern to that of the control. However, the group treated with CPE in PB-challenged showed a significant decrease in the activities of ALP, ALT, AST, GGT, LDH and total bilirubin as compared to the CN in a dose-dependent manner. In addition, CPE also restored GSH level as well as decreased MDA level in PB- challenged group. These biochemical results were reflected in the histological evaluation of the tissue samples. Hence, CPE ameliorates PB-induced hepatotoxicity by regulating its toxic insults and oxidative stress.
Keywords
Calotropis procera extract
Hepatotoxicity
In Vivo
Oxidative stress
Potassium bromate
1. Introduction
Hepatotoxicity, or liver damage, caused by chemicals, particularly those used in food processing, remains a major concern in environmental and clinical toxicology (Singh et al., 2011). As the primary organ for metabolism and detoxification, the liver is particularly vulnerable to injury from toxicants, including therapeutics, environmental toxins, and industrial chemicals (Bischoff et al., 2018). Among these, recent studies have implicated potassium in causing hepatotoxic effects, often through mechanisms involving oxidative stress and inflammation (Aminjan et al., 2019). Potassium bromate (KBrO3) is a carcinogen and is widely used as an oxidising agent in the food industry. Its exposure can lead to oxidative stress, resulting in cellular damage and various health issues (Islam et al., 2024). KBrO₃ is a powerful oxidizing agent that reacts with organic materials and is classified by the International Agency for Research on Cancer (IARC) as a possible human carcinogen.
Calotropis procera (CP) is a wild shrub native to North Africa and Asia that has been the subject of much research due to its therapeutic attributes (Singh et al., 2024). It contains various bioactive compounds such as tannins, glycosides, phenols, and alkaloids, contributing to its therapeutic potential (Zafar et al., 2021). A study by Chang et al. has demonstrated that C. procera possesses various pharmacological properties, such as anticonvulsant and analgesic effects (Chang et al., 2021). Additionally, a study by Bharti et al has shown the protective effects of C. procera extracts (CPE) on gastric ulcers induced by various factors (Bharti et al., 2010). Furthermore, researchers have investigated the anticonvulsant effects of CPE, suggesting their potential in managing convulsive disorders (Chang et al., 2021). Moreover, CPE has been shown to mitigate kidney damage induced by potassium compounds (Ogunmoyole et al., 2023). Researchers have also studied CPE for its antioxidant properties and protective effects against PB-induced oxidative stress (Al-Snafi, 2016; Kanwar et al., 2023) and have found therapeutic significance in traditional medicine, against ulcers, and hepatoprotective effects (Lotfy et al., 2020). The biomass of CP fruits is highly effective at absorbing the MB dye from aqueous environments due to several properties of its activated carbon (Benaddi et al., 2024). Another study used CP fruit biomass as a supporting material to produce activated carbons for supercapacitor electrodes (Benaddi et al., 2025).
Through oxidative stress, inflammatory responses, and disruption of cellular signalling pathways, PB is toxic to the liver, causing hepatic dysfunction (Nivetha et al., 2024). Exposure to PB causes an increase in ROS production and lipid peroxidation, protein damage, and DNA damage, all of which contribute to the death of liver cells, primarily by necrosis and some by apoptosis (Li et al., 2021). Significant oxidative damage has been found in liver tissues after exposure to PB, as shown by an increase in malondialdehyde (Al-Mareed et al., 2022).
Pyrrolidine and 1,3-cyclopentanedione are organic compounds found in CPE. Pyrrolidine derivatives were found to have potential antibacterial bioactivities (Bhat 2024). CPE from flowers contains flavonoids, which have antioxidant and hepatoprotective properties (Qureshi et al., 2007; Shehab et al., 2015; Sombié et al., 2020). However, there has been little research on the effects of PCE on PB-induced hepatotoxicity. CPE’s anti-inflammatory, analgesic, and antioxidant properties have been used in many herbal medicines.
The study hypothesizes that CPE, which contains diverse bioactive compounds such as tannins, glycosides, phenols, and alkaloids, may be able to counteract PB- PB-toxicity due to its well-known anti-inflammatory, analgesic, and antioxidant properties. The study delves into the specific effects of CPE on liver function markers and oxidative stress indicators in a controlled in vivo environment, aiming to fill the gap in the existing literature.
2. Material and Methods
2.1 Chemicals
All the KBrO₃ chemicals were procured from Sigma Aldrich (Louis, MO, USA). PBS was from Millipore (Merck KGaA, Darmstadt, Germany). The kits for biochemical use were bought from Química Clínica Aplicada diagnostic kits (Apdo, Amposta, Tarragona, Spain).
2.2 Gas chromatography-mass spectrometry (GC-MS) method
To prepare samples, we used 0.25 g of CPE and dissolved it in 1 mL of hexane. After that, 0.2 mL of sodium hydroxide solution in methanolic (1 M) was added and heated with shaking at a temperature of 45°C. Then 0.2 mL of methanolic hydrochloric acid solution (1 mL) was added, shaking and leaving the solution until the layers separated. The organic layer was taken, diluted with 0.5 mL hexane, and injected directly.
Through the use of the database-integrated software, the items were recognised. The RT-2560 capillary column, manufactured by Restek, separated target compounds. It had a length of (100 m length × 0.25 mm internal diameter, phase thickness 0.2 μm). Helium was used as the carrier gas, and the flow rate was 1 mL/m. The inlet temperature was 250°C, with a split mode ratio of 50. The oven temperature ranged from 50 to 250°C, and the total analysis time was 77 min. Acquisition scan type, mass range from 40 to 500 g/mol, scan speed 1.56, 9-min solvent delay, and 230°C MS source temperature were the parameters that were selected for the mass spectrometer (MS) detector.
2.3 Animals
We selected adult male Wistar Rats (140-150 g and 3 months old) from the animal house of the Department of Zoology, KSU, KSA. The rats were fed a standard pellet diet and fresh tap water ad libitum and housed at an adjusted temperature (22 ± 1°C; 73–76% relative humidity; 12 h light-dark cycle).
2.4 Study design
We randomly divided the 25 rats into the following five groups: Group (CN): the vehicle control group that received PBS. Group): administering a single dose of potassium bromate at a concentration of 150 mg/kg body weight (Hassan et al., 2020). Group (CPE): a dose of 2 mg/kg body weight twice a week for 1 month. Group (PB+CPE 2 mg/kg): a single dose of PB at 150 mg/kg body weight for the PB group, followed by the dose of CPE at 2 mg/kg and at 4 mg/kg body weight twice weekly for a month. In this study, we administered all of the test substances intraperitoneally and sacrificed the same day after the therapy ended to collect biological samples. The research received approval from KSU’s Departmental Ethical Committee for Zoology.
2.5 Sample collection
Drawing blood from rats through cardiac puncture according to the (Beeton et al., 2007) method, 4 mL was collected in EDTA tubes. We isolated the plasma by centrifuging it at 4000 g for 15 min, and one part was stored in the refrigerator; the other was stored at −80°C. Then we collected the liver samples after washing them with PBS.
2.6 Liver homogenate
The part liver was weighed and homogenized in Tris-KCl buffer (pH 7.36) on ice (Ika-Werke, Germany). Their supernatants were centrifuged at 5000 g for 15 min, then divided into two parts: one part was used at the same time for the assessment of the reduced glutathione (GSH), and the other was kept at −80°C until evaluation of malondialdehyde (MDA). In addition, we preserved half of each animal’s liver for histopathological analysis.
2.7 Assessment of liver function markers
The commercial kits (Quiccia Clnica Aplicada diagnostic kits, Spain) carried out the assays of ALT, AST, ALP, GGT, total bilirubin, and LDH in plasma following the manufacturer’s instructions. The colorimetric method measured their levels kinetically.
2.8 Measurement of reduced glutathione (GSH) level
To ascertain the total amount of reduced glutathione (GSH), the technique described by Jollow et al. (1974) was used.
2.9 Assessment of malondialdehyde (MDA)
The total quantity of MDA, an indicator of oxidative damage to lipids, was measured using the standard methodology developed by (Buege and Aust 1978).
2.10 Determination of oxidatively modified proteins
For detecting and measuring the oxidative alteration of proteins, we used the methodology of Levine et al. (1994) to determine the oxidatively modified proteins in the liver.
2.11 Histopathological examinations
Liver tissues were fixed in 10% formalin and then were cut into 6 μM sections. Sections were stained with H & E (Anwar et al., 2020). Evaluation of the prepared slides was done blindfolded using a light microscope (Leica DMRB/E Heerbrugg, Switzerland) paired with an HD camera (Leica MC 170 HD, Singapore). Adobe Photoshop (Adobe Systems, Mountain View, CA, USA) digitally improved the photomicrographs of the sections shot at 200×.
2.12 Statistical analysis
The data have been presented as the mean ± SD and analysed using SPSS and GraphPad Prism 5 software. The data underwent a one-way ANOVA analysis accompanied by a Bonferroni multiple comparison test. A p-value of less than 0.05 was established as statistically significant in this study. The symbol “*” was employed as an asterisk to indicate significant differences from the negative control (CN−, group I), whereas the symbol “#” was utilized as an asterisk to denote significant differences from the positive control (CN +, group II).
3. Results
3.1 GC-MS analysis
Fig. 1 presents the results of a GC-MS analysis, which identifies and quantifies various chemical compounds in C. procera extracts. Here’s a detailed description of the results: The CPE analyzed contains a complex mixture of organic compounds, with 1,3-Cyclopentanedione, 4-(3-methylbutyl)- being the most abundant. The second most abundant compound is 2,3-Bis (1-methylallyl) pyrrolidine, making up 13.14% of the total area. In addition, the table shows a wide variety of chemical classes, including Aldehydes (2,4-Heptadien-6-ynal, (E, E)-, Alcohols (Phytol), Ketones (2-Pentadecanone, 6,10,14-trimethyl-), Esters (Hexadecanoic acid, methyl ester), Acids (Myristoleic acid), Hydrocarbons (6-Tridecene), Heterocyclic compounds (2,3-Bis(1-methylallyl) pyrrolidine).
- GC–MS chromatogram of the methanolic extract of Calotropis procera
Peaks correspond to compounds identified by comparison with the NIST library. The x-axis represents retention time (min), and the y-axis represents relative abundance (%).
3.2 Effect on liver function markers
3.2.1 Alkaline phosphatase (ALP)
ALP is an essential enzyme for evaluating liver function in living organisms. Groups PB and CPE demonstrated a significant increase in their activity by 286.21% and 31.05%, respectively, as compared to the CN group. However, in the PB group, treatment with CPE was found to restore the ALP values close to the CN levels. CPE decreased its activity by 46.47% and 55.85%, as evidenced by the groups- PB+ CPE (2 mg/kg) and PB+ CPE (4 mg/kg), respectively (Fig. 2) in comparison to the PB rats.
- ALP levels in the CN (control), PB (potassium bromate), CPE (Calotropis procera extract), PB+CPE+2 mg/kg, and PB+CPE+4 mg/kg groups.
3.2.2 Alanine transaminase (ALT)
In the present investigation, the ALT levels showed that groups PB and CPE showed an elevation of their activity by 228.82% and 59.45% relative to the control. In the PB group, treatment with CPE was found to restore the ALT values close to the CN levels. Groups- PB+ CPE (2 mg/kg) and PB+ CPE (4 mg/kg), displayed a decline in their activity by 41.53% and 55.33% as compared to group PB (Fig. 3) in comparison to the PB rats.
- ALT levels in the CN (control), PB (potassium bromate), CPE (Calotropis procera extract), PB+CPE+2 mg/kg, and PB+CPE+4 mg/kg groups. * indicating a significant difference from the CN and # indicating a significant difference from group PB. * indicating a significant difference from the CN and # indicating a significant difference from group PB.
3.2.3 Aspartate transaminase (AST)
The enzyme activity in groups PB and CPE was higher by 176.01% and 2.02%, respectively, relative to the CN rats. In the PB group, treatment with CPE was found to restore the AST values close to the CN levels. However, the activity of AST dropped by 34.32% and 55.12% in groups- PB+ CPE (2 mg/kg) and PB+ CPE (4 mg/kg), in comparison to the PB rats (Fig. 4).
- AST levels in the CN (control), PB (potassium bromate), CPE (Calotropis procera extract), PB+CPE+2 mg/kg, and PB+CPE+4 mg/kg groups. * indicating a significant difference from the CN and # indicating a significant difference from group PB.
3.2.4 Gamma-glutamyl transferase (GGT)
Groups PB and CPE showed an increase in GGT activity by 164.54% and 6.09%, respectively, compared to the CN. In comparison, the groups- PB+ CPE (2 mg/kg) and PB+ CPE (4 mg/kg), exhibited a decline in their activity by 34.32% and 55.12%, respectively, as compared to group PB (Fig. 5).
- GGT levels in the CN (control), PB (potassium bromate), CPE (Calotropis procera extract), PB+CPE+2 mg/kg, and PB+CPE+4 mg/kg groups. * indicating a significant difference from the CN and # indicating a significant difference from group PB.
3.3 Total bilirubin
Bilirubin testing is essential for evaluating liver health. In groups PB and CPE, total bilirubin increased by 173.63% and 34.54%, respectively, compared to the CN. In comparison, the groups PB+ CPE (2 mg/kg) and PB+ CPE (4 mg/kg) exhibited a decline in their activity by 34.88% and 45.84%, respectively, as compared to group PB (Fig. 6).
- Bilirubin levels in the CN (control), PB (potassium bromate), CPE (Calotropis procera extract), PB+CPE+2 mg/kg, and PB+CPE+4 mg/kg groups. * indicating a significant difference from the CN, and # indicating a significant difference from group PB.
3.4 Reduced glutathione (GSH)
Reduced glutathione is a vital antioxidant that plays multiple roles in cellular protection, detoxification, and metabolic processes. Compared to group CN, the levels of GSH in the PB and CPE groups dropped by 60.09% and 11.63%, respectively. However, its levels increased in groups-PB+ CPE (2 mg/kg) and PB+ CPE (4 mg/kg) by 60.12% and 100.59%, respectively, with respect to PB (Fig. 7).
- GSH levels in the CN (control), PB (potassium bromate), CPE (Calotropis procera extract), PB+CPE+2 mg/kg, and PB+CPE+4 mg/kg groups.
3.5 Lactate dehydrogenase (LDH)
Compared to group CN, lactate dehydrogenase levels in groups PB and CPE dropped by 131.81% and 13.75%, respectively. However, the levels in groups- PB+ CPE (2 mg/kg) and PB+ CPE (4 mg/kg) were significantly increased by 32.31% and 42.47%, respectively, when it came to group PB (Fig. 8).
- LDH level in the CN (control), PB (potassium bromate), CPE (Calotropis procera extract), PB+CPE+2 mg/kg, and PB+CPE+4 mg/kg groups. * indicating a significant difference from the CN and # indicating a significant difference from group PB. * indicating a significant difference from the CN and # indicating a significant difference from group PB.
3.6 Effect on macromolecular oxidation
3.6.1 Malondialdehyde (MDA)
In the present investigation, groups PB and CPE increased their levels by 115.51% and 36.84%, respectively. CPE was found to significantly decrease Malondialdehyde levels by 19.15% and 26.99% in groups- PB+ CPE (2 mg/kg) and PB+ CPE (4 mg/kg) in comparison to group PB (Fig. 9). The levels of Malondialdehyde in both PB+ CPE treated groups were partially restored to the control values.
- MDA level in the CN (control), PB (potassium bromate), CPE (Calotropis procera extract), PB+CPE+2 mg/kg, and PB+CPE+4 mg/kg groups. *indicating a significant difference from the CN and #indicating a significant difference from group PB.
3.6.2 Total protein content
In the present study, the total protein content showed no significant results between all groups (Fig. 10) in any of the investigated rat groups.
- Total protein level of the different animal groups in g/dl. * indicating a significant difference from the CN and # indicating a significant difference from group PB.
3.7 Histopathological examination
The normal liver’s control micrograph is shown in (Fig. 11a) with the known distribution of polygonal hepatocytes with typical nuclei. The hepatic sinusoids typically exhibit peripheral Kupffer cells. Significant pathological changes were noted in the hepatic tissues of the PB-challenged rats (Fig. 11b). Histological investigations revealed altered architecture, with hepatocytes exhibiting pale eosinophilic cytoplasm devoid of significant granulation in contrast to normal sections. In the same group, PB-challenged rats exhibited smaller sinusoidal gaps than usual, attributable to the atypical distribution of hepatocytes in this cohort. Mild pathological changes have been unexpectedly identified in rats treated alone with CPE in the liver sections. Analysis of the liver sections indicated somewhat constricted sinusoids with a moderately altered architecture and the presence of eosinophilic hepatocytes (Fig. 11c). Hepatic tissue improvement is noted in PB-challenged rats administered CPE at a dosage of 2 mg/kg body weight. The examination of this group revealed moderate histopathological changes, including mild infiltration of inflammatory cells and narrowed sinusoids. Fig. 11(d) clearly demonstrates that the histological alterations in the hepatic tissues of PB-challenged rats administered CPE at 2 mg/kg of body weight were equivalent to those of the control group (Fig. 11a). Wide sinusoids with mild inflammatory cell infiltration and vesiculated nuclei are seen in PB-preexposed rats administered with CPE at 4 mg/kg body weight (Fig. 11e).
- (a) Photomicrographs represent hepatic tissues from control rats, (b) Potassium promote challenged rats, (c) Rats treated with CPE 2 mg/kg of body weight, (d) Potassium promote challenged rats treated with CPE 2 mg/kg of body weight, (e) Potassium promote challenged rats treated with CPE 4 mg/kg of body weight from. The major histological alteration indicated the central veins (triangles), hepatocytes (thick blue arrows), sinusoidal spaces (yellow arrows), Kuppffer cells (red arrows) and inflammatory cells (black arrows). The sections were snapped under at a scale bar of 50 μm.
4. Discussion
Most populations in developing countries use herbal plants for healthcare needs (Nsagha et al., 2020). C. procera has been attracted to the scientific community because of its antioxidant, anti‐inflammatory, and neuroprotectant properties (Mali et al., 2019; Paul et al., 2018). Thus, it can be hypothesised that the phytoconstituent components of C. procera may effectively promote hepatotoxicity.
The ALP, ALT, and AST are essential for evaluating liver and biliary function. They play critical roles as biomarkers of liver inflammation, damage, and injury. The notable elevation in the activity of enzymes- ALP, ALT, and AST in group PB. The significant increase in these enzymes in the PB group indicates early indicators of liver damage. The liver, as the primary organ for metabolism and detoxification, is particularly vulnerable to PB-induced toxicity, which consequently causes hepatotoxicity. This study demonstrates that the significant decrease in the activity of these enzymes after CPE treatment suggests that the extract has a therapeutic effect against liver damage. This finding aligns with the findings of (Lala et al., 2023) and (Kalas et al., 2021). Nevertheless, the reduction in activity seen after the treatment with CPE suggests that CPE may have a therapeutic effect against liver damage. The study also indicates that CPE may aid in the process of recovering from liver injury, aligning with the function of these enzymes as markers of liver inflammation and damage (Aladejana and Aladejana 2023, Rabelo et al., 2023).
GGT is particularly a sensitive biomarker for assessment of liver damage and biliary obstruction (Kalas et al., 2021). The increase in GGT activity in group PB, followed by a reduction in treated groups, further supports the hypothesis that CPE may mitigate liver injury and restore its function, reflecting the enzyme’s role in detoxification and cellular protection. This result is consistent with the results of previous studies (Yap and Aw 2010, Fahim et al., 2016). Elevated bilirubin levels can indicate liver dysfunction, particularly in the context of cholestasis. The increase observed in groups PB and CPE, followed by decreases in treated groups, suggests that CPE may help restore normal bilirubin metabolism, thus indicating improved liver function (Yap and Aw 2010, Levick 2017, Lala et al., 2023). This is also proved by the improvement in the hepatic structure of the PB treated with CPE.
Oxidative stress has a well-established role in the aetiology of liver disorders. Oxygen and nitrogen species induce cellular damage, lipid peroxidation, and liver injury. (Bashandy et al., 2023, Ebaid et al., 2023, Hassan et al., 2023; Hassan et al., 2024). GSH is a critical antioxidant that protects against oxidative stress by neutralising free radicals (Averill-Bates 2023). It is documented that the decline in GSH leads to an elevation in free radicals along with an increase in lipid peroxidation and reduced SOD activity (Jena et al., 2012). The 2-Here, we found that 1,3-cyclopentanedione is the most common compound in the C. procera. The ingredient significantly decreased malignant cell proliferation and induced apoptosis by inhibiting atypical protein kinase C isoforms (PKCs) that trigger the translocation of NF-κB to the nucleus (Diaz‐Meco and Moscat 2012). This might finally reduce the oxidative stress and restore the oxidative stability in vivo. Overall, the results suggested that this compound can be effectively used as a potential inhibitor in targeted therapy (Diaz‐Meco and Moscat 2012). The study found that treatment with CPE significantly restored these levels, which suggests that CPE protects liver cells and enhances the liver’s antioxidant capacity and function (Ahmad Nejhad et al., 2023; Nisar et al., 2024).
According to Farhana and Lappin (2020), lactate dehydrogenase is an enzyme produced during tissue injury. CPE, in the present study, helped in tissue regeneration and also minimized cellular damage, as shown by the combination treatment groups. This finding lends credence to the concept that oxidative stress plays a key role in liver injury (Sawong et al., 2022; Kumar and Yogesh).
According to Mohideen et al. (2023), MDA is a marker of oxidative stress and lipid peroxidation together. The current study shows that CPE has protective effects against oxidative damage, as demonstrated by the increases in MDA levels in PB, and the same was found in reductions in treatment groups (Kumar and Roy 2007, Kumar et al., 2021, Ogunmoyole et al., 2023; Hassan et al., 2025). These results show the significance of antioxidants in maintaining healthy liver function.
5. Conclusions
Our findings suggest that the administration of potassium bromate led to a significant increase in liver enzyme levels (ALP, ALT, AST, and GGT), as well as total bilirubin, indicating liver stress and damage. Treatment with CPE effectively restored the activities of these enzymes and bilirubin levels to near-normal in a dose-dependent manner. These suggest that CPE has a strong therapeutic potential to heal the PB or similar toxicant-induced liver damage. Future research should prioritize investigating the mechanisms via which CPE exerts its protective properties and examining its potential therapeutic uses in liver diseases.
CRediT authorship contribution statement
Jameel Al-Tamimi and Hossam Ebaid conceived the study. Jameel Al-Tamimi and Hossam Ebaid provided the study concept and design, while Iftekhar Hassan and Jameel Al-Tamimi were responsible for data acquisition, analysis, and statistical evaluation. Jameel Al-Tamimi and Hossam Ebaid prepared the first draft of the introduction and discussion, whereas Iftekhar Hassan and Jameel Al-Tamimi drafted the methods and results sections. The final manuscript was critically reviewed and edited by Jameel Al-Tamimi, Iftekhar Hassan, and Hossam Ebaid. Ahmed Rady helped in animal handling while Ibrahim Alhazza supervised the research work and related permissions.
Declaration of competing interest
The authors declare that they have no competing financial interests or personal relationships that could have influenced the work presented in this paper.
Data availability
This published paper includes all of the data collected or analyzed during the course of this study.
Declaration of Generative AI and AI-assisted technologies in the writing process
The authors confirm that there was no use of artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript and no images were manipulated using AI.
Funding
This work was supported by Researchers Supporting Project number (ORF2025R366), King Saud University, Riyadh, Saudi Arabia.
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