INTRODUCTION:

Several anti-cancer medications have serious side effects in addition to their therapeutic benefits. A significant number of therapeutic candidates may fail to advance to clinical development owing to toxicity¹. As a result, the scientific community strives to provide a safe medicine with minimum side effects on humans. Some of the medications are harmful to the placenta. In a broader sense, trans-placental toxicity refers to the toxic consequences detected in a fetus or progeny as a result of maternal chemical or pharmacological exposure².

Despite therapeutic options, many medications have harmful side effects. Drug-induced liver injury is a possible side effect of numerous medications. This is not surprising because the liver is essential to how most drugs are metabolized². Prospective cohort of 185 patients with a diagnosis of drug induced liver damage was collected (2000 January to 2016 December) and the mean age was 53 years, even though about 70% of the patients were under 40 years^3,4. Only 2% of the patients had a history of chronic liver disease. At the time of clinical presentation, 57.8% of cases displayed a hepatocellular pattern, 18.3% a cholestatic pattern, and 23.2% a mixed pattern. 23.4% of cases involved antibiotics, 35.5% involved NSAIDs, 10.9% involved immunosuppressants, 4.3% involved statins, 7.6% involved anti-platelet and anti-psychiatric medications, and 9% involved other medications. In terms of evolution, immunosuppressants, NSAIDs, and antibiotics frequently contributed to chronicity, but statins, anti-psychiatric medications, and anti-platelet medications did not. (Figure. 1)

Figure No: 1 Drug induced hepatotoxicity in patients with mean age of 53 years

The swertiamarin was therefore taken into consideration for the current investigation in order to explore its potential protective benefits against Ara-C-induced hepatotoxicity in maternal liver of SD rat. The toxic effects of the medicine are also affected by factors such as the type of the toxicant, the duration of exposure, the gestational period, and any antioxidant supplements⁵. Many changes will occur in the mother before and throughout pregnancy to prepare her for pregnancy and to keep the pregnancy going. During pregnancy, the following critical events occur: increased cardiac output, increased blood volume in the body, and retention of the chemicals necessary for water retention⁶. Vascular resistance will be lowered as well, allowing for smooth blood flow. These alterations will peak in the second trimester and last until parturition.

Cytarabine (Ara-C) is a widely used anti-neoplastic medication. It is thought to be an anti-metabolite medication. It is primarily used as a primary therapy for blood malignancies, particularly acute myeloid leukemia and non-Hodgkin lymphoma⁷. Several changes occur in the mother's liver throughout pregnancy to meet the demands of both the mother and the developing child. Many biochemical features of the liver, including as alkaline phosphatase (ALP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST), have been observed to increase in maternal and even fetal liver⁸. Patients who had Ara-C medication as part of their cancer treatment also had abnormally high levels of creatinine, blood urea nitrogen (BUN), and renal function impairment⁹. In individuals treated with modest doses of Ara-C, abnormalities in liver function have been documented. Ara-C at high dosages was also found to produce significant hepatotoxicity. Ara-C has also been found to be clastogenic, causing DNA damage, apoptosis, and the creation of micronuclei as a result of DNA fragmentation. Ara-C was also discovered to be a source of genetic toxicity, namely DNA damage. Several researches on the effects of Ara-C on normal adult rats have been conducted. However, no studies have been conducted to investigate the effects of Ara-C on the maternal liver. As a result, we conducted a research to assess the effects of Ara-C on maternal liver in Sprague Dawley (SD) rats¹⁰. Ara-C has been shown to increase free radicals, which are extremely reactive and interact with important components of the body, impairing their function and eventually leading to an increase in oxidative stress. As a result, it is important to utilize medicines that minimize oxidative stress caused by Ara-C to lessen Ara-C harmful effects¹¹.

Enicostemma axillare Raynal (Syn. Enicostemma littorale Non Blume) (Family Gentianaceae) is a perennial glabrous plant found in coastal locations across India¹². The herb has long been used to treat liver ailments and as a blood purifier¹³. Enicostemma axillare was used to isolate alkaloids, steroids, saponins, triterpenoids, flavonoids, phenolic acids, and xanthones¹⁴. Swertiamarin is a secoiridoid glycoside containing molecular formula C₁₆H₂₂O₁₀ and are monoterpenoids with the skeleton of 7, 8-secocyclopenta [c] pyranoid. These are found in many plant families and are present in a variety of folk medicinal herbs used as bitter tonics, sedatives¹⁵, antipyretics¹⁶, and hypotensives, among other things. Swertiamarin, a bitter secoiridoid glycoside, has been shown to have antibacterial, brine shrimp lethality, anticholinergic, and antihyperlipidaemic¹⁷ properties. Swertiamarin has been shown in studies to have powerful antiedematogenic and antinociceptive¹⁸ effects.

MATERIALS AND METHODS:

Drugs and chemicals:

Cytarabine and swertiamarin were bought from Sigma Aldrich in the United States. All additional (analytical grade) chemicals used in the experiment were acquired locally.

Experimental animals:

The female SD rodents (rats) that are in estrous, or in heat, and have a body weight of roughly 200grams were chosen, and they are permitted to mate in a 2:1 ratio with SD male rats weighing 250g. Rats with a vaginal plug or sperm remains or residues in the vagina or on the origin of the vagina or when a vaginal smear was examined under a microscope were considered as pregnant. Animals were thoroughly acclimatized for one week prior to begin animal trials.

Research methodology:

A total of 48 SD female rats were randomly distributed into six groups (8 animals in each group). Experimental animals received various ST dosages formulated in 0.3% carboxy methyl cellulose (CMC) through oral administration. As a control, Group I was given normal saline-orally, Group II was given Ara-C 25mg/kg/day-orally, Group III and IV were given ST (100 and 200 mg/kg/day)-orally. Group V and VI were given Ara-C 25mg/kg/day-orally as well as ST supplementation 100 and 200mg/kg/day-orally for a period of 13 days from GD8 to GD20.

Biochemical tests:

The animals were euthanized and subsequently slaughtered when the treatment time was completed. To avoid any procedure harm, the liver tissues were harvested with considerable caution. Part of liver tissues were utilized for histological analysis, while the remainder of each rat's liver was homogenized in 0.1-M-phosphate-buffer (pH 7.4) containing 3-mM-EDTA and centrifuged at 4°C, 7000g for 7m. The resulting plasma was employed in biochemical assays. Blood samples were collected through retro-orbital sinus puncture and the plasma were examined for the activity of the enzymes AST, ALT, Urea¹¹, and Creatinine¹² by Using Ranbaxy Fine Chemicals Limited diagnostic kits (India).

Oxidative stress estimated by malondialdehyde (MDA)¹³, superoxide dismutase (SOD)¹⁴, catalase (CAT)¹⁵, glutathione (GSH)¹⁶ and glutathione peroxidase (GSH-Px)¹⁵ by U.V. absorbance at wavelength 532-750nm. The animals were treated humanely throughout the investigation, and the work was authorized by the Institutional animal ethics committee on ethical standards in animal experiments.

Histopathology:

Histopathological slides were used to examine histological alterations. Slides made in accordance with our laboratory's established technique. The livers of pregnant dam rats were fixed in 10% formalin fixing solution, then dried (reduction of water content to inhibit bacterial development) in increasing concentrations of ethanol, and embedded in heated then hardened paraffin¹⁷. Tissue slices 5m thick were put on a glass slide coated with Mayer's albumin and left to dry for about 12hours (overnight). The sections put on the slides were de-paraffinized with an organic solution called xylene, then rehydrated with a specific ratio of alcohol, primarily ethanol, and water. These rehydrated tissue slices were then stained for differential staining with H&E, mounted with DPX mounting solution, and carefully scrutinized under the microscope for histological alterations, modifications, or aberrations¹⁸.

Statistical analysis:

As all the data were calculated and expressed in mean± SEM. Sigma Stat (Version 5.3) was used to perform all study-related calculations. ANOVA used to determine the multiple comparisons significance.

RESULTS AND DISCUSSION:

Evaluation of body weight:

The increased weight (from GD8 to GD21) of dams treated with normal saline, ST (100 and 200mg/kg) indicated normal body-weight gain. Dams treated with Ara-C (group II) displayed a lower weight growth when compared to dams in the control groups (p<0.01). Interestingly, as compared to dams treated with Ara-C alone (p<0.01), the intervention group treated with Ara-C plus ST (groups V and VI) displayed better body weight growth (p<0.01) (Figure.2).

Evaluation of oxidative stress:

Animals exposed to the test drug Ara-C (group-III) in pregnant rats resulted in a situation in which the oxidative stress marker MDA levels were significantly increased while other oxidative stress markers such as CAT, GSH, GPx, and SOD levels were significantly decreased when compared to dams administered with normal saline (p<0.01). However, dams supplied with a combination of ST and Ara-C (groups V and VI) nearly completely restored these aberrations or imbalances (p<0.01) (Table. 1) (Figure. 3).

Evaluation of liver function markers:

The animals given normal saline, ST (100 and 200 mg/kg) had normal AST, ALT, urea, and creatinine levels. Ara-C (group II) treatment to dams resulted in a substantial increase in AST, ALT, urea, and creatinine levels (p<0.01). However, when Ara-C was combined with ST (groups V and VI), the unfavorable effects were reduced (p<0.01) (Table. 2) (Figure. 4).

Histopathology:

The testing medication is primarily metabolized in the liver. As a result, compounds are detrimental to cells because greater damage to liver cells and the Ara-C impact on the liver is evident. The test medication Ara-C (group II) (p<0.01) induced vacuolization, architectural aberrations, and a significant increase in pycnotic nuclei, as well as dilated sinusoids in dams' fetuses. Surprisingly, harmful foot prints were not found in Dam progeny treated with normal saline and a protective substance. The harmful effects of Ara-C on the liver were reversed in the offspring of dams treated with ST (groups V and VI) (Figure. 5).

Table 1: Effect of swertiamarin and cytarabine on MDA, CAT, GSH, GSH-Px, SOD levels.

Oxidative stress markers

MDA (mM/mg protein)

CAT (µmol of H2O2/min/mg protein

GSH

(µmol/mg protein)

GSH-Px

(units/mg protein)

SOD (µmol of H₂O₂/min/mg protein)

Control

Ara-C

ST-100

ST-200

AraC + ST100

AraC + ST200

0.01±0.001

0.03±0.001**

0.01±0.001

0.01±0.001^##

0.45±0.02

0.22±0.04**

0.43±0.02

0.45±0.01

0.36±0.04^##

0.38±0.03^##

0.05±0.003

0.02±0.003**

0.06±0.002

0.05±0.003

0.05±0.003^##

0.05±0.002^##

11.58±1.06

6.60±0.97**

11.70±0.53

11.92±0.51

9.5±1.35^##

10.5±1.07^##

34.90±3.76

23.50±2.98**

42.51±2.60

43.40±2.50

36.58±3.02^##

35.58±2.50^##

Data were calculated and expressed in mean ± SEM (n = 8). ANOVA used to determine the multiple comparisons significance. **P < 0.01 and *P < 0.05 vs. Control. ##P < 0.01 and #P < 0.05 vs. cytarabine (25 mg/kg).

Table.2. Effect of swertiamarin and cytarabine on AST, ALT, Urea, Creatinine levels.

Enzyme markers	AST (U/L)	ALT (U/L)	Urea (mg/dl)	Creatinine (mg/dl)
Control	28.52±6.87	66.65±9.75	11.51±2.95	0.24±0.05
Ara-C	47.68±3.58**	88.88±7.78**	20.52±2.3**	0.36±0.06**
ST-100	25.95±5.14	54.39±10.84	12.3±2.74	0.25±0.04
ST-200	24.89±4.55	52.40±9.89	11.4±2.53	0.23±0.03
AraC + ST100	30.81±4.85^##	63.28±11.87^##	14.37±2.1^##	0.29±0.04^##
AraC + ST200	28.82±4.97^##	60.25±10.07^##	12.22±2.3^##	0.26±0.02^##

Figure No: 2 Effect of swertiamarin and cytarabine on maternal body weight gain. (A) Maternal body weight gain of all groups. (B) Maternal body weight gain from GD7-GD14 and GD15-GD20. (C) and (D) Maternal body weight gain on GD7, GD14 and GD20. All the values are expressed as mean±SEM, (n = 8), **P < 0.01 and *P < 0.05 vs. Control. ##P < 0.01 and #P < 0.05 vs. cytarabine (25 mg/kg).

Figure No: 3 Effect of swertiamarin and cytarabine on MDA, CAT, GSH, GSH-Px, SOD levels. (A) Malondialdehyde, (B) Glutathione, (C) Catalase, (D) Glutathione peroxidase, and (E) Superoxide dismutase. All the values are expressed as mean± SEM, (n = 8), **P < 0.01 and *P < 0.05 vs. Control. ##P < 0.01 and #P < 0.05 vs. cytarabine (25mg/kg).

Figure No: 4 Effect of swertiamarin and cytarabine on treatment on AST, ALT, Urea, Creatinine levels. (A) Aspartate aminotransferase, (B) Alanine aminotransferase, (C) Creatinine, and (D) Urea. All the values are expressed as mean ± SEM, (n = 8), **P < 0.01 and *P < 0.05 vs. Control. ##P < 0.01 and #P < 0.05 vs. cytarabine (25 mg/kg).

Figure No: 5 Effect of swertiamarin and cytarabine on liver histopathology. (A) Control group, (B) Cytarabine group (Ara-C), (C) Swertiamarin group (ST- 100 mg/kg) (D) Swertiamarin group (ST- 200 mg/kg) (E) Intervention group (Ara-C+ ST-100) and (F) Intervention group (Ara-C+ ST-200)

Ara-C is a potential medication for the treatment of a wide range of diseases, particularly blood cancers. It is used as single therapy (alone) or as combination therapy (together with other medications). It is utilized as a cornerstone therapy for acute myeloid lymphoma and other types of blood malignancies⁷; however it is also linked with significant toxicity. In recent years, attempts have been made to lessen the toxicity associated with the majority of medications⁵. Using Ara-C to treat blood cancer poses a significant toxic insult and has severe toxic effects on the liver, one of the body's most important and necessary organs⁴. Previous research revealed that Ara-C exposure causes liver damage, as well as inflammatory pathways in the liver and cell death. Several publications in the public scientific literature indicate that Ara-C has clastogenic potential, causes oxygen free radical production, and may induce apoptosis, all of which help to support its cytotoxic effect⁷. Ara-C can also induce chromosomal aberrations, which are changes in the number and structure of chromosomes, affects DNA as well, causing a variety of undesirable effects¹⁰.

The abnormalities in body weight increase and liver weights in pregnant rats exposed to Ara-C clearly indicated the toxic manifestations of Ara-C. We saw hepatocellular deterioration that resulted in vacuolisation. Furthermore, the hepatotoxic potential of Ara-C was clearly obvious in the assessment of liver function indicators. Ara-C has clearly increased the ALT and AST values, indicating toxicity. Any deviations in ALT and AST values suggest impairment in liver function; hence they are commonly used as liver function tests. There is a connection between liver function and renal function⁷. In our investigation, we found a significant rise in urea levels, indicating that Ara-C is hazardous to the liver⁸. The histological evaluation performed in our study revealed morphological changes, indicating disarray of the hepatocytes and related structures such as sinusoids. In our investigation, Ara-C therapy resulted in a significant rise in the percentage of injured cells. Oxidative stress was clearly elevated, as evidenced by the levels of MDA. Ara-C has also been shown to impair anti-oxidant pathways in pregnant rats⁹. This assertion is based on significant decreases in indicators of anti-oxidant systems. Moreover, the test medication in this study, Ara-C, has genotoxic potential¹⁹. The most modern and reliable tests, however, are the comet assay, TUNEL assay, Micronucleus assay, and chromosomal abnormalities testing. All of the foregoing experiments revealed that Ara-C was genotoxic¹⁰.

According to our findings, Ara-C has the potential to cause hepatotoxicity. The liver of pregnant dams, in particular, synthesizes many substances required for pregnancy growth and maintenance. As a result of our findings, pregnant rats exposed to Ara-C are inefficient in maintaining their pregnancies and have poor pregnancy outcomes. The appropriate growth and functioning of both the maternal and fetal livers is critical for pregnant rats to execute their roles during pregnancy and for the development of the fetus^20-22. As a result, our findings are consistent with previous research on the hazardous potential of Ara-C^23-25. According to our understanding, this is the first study to look at the harmful potential of Ara-C on the maternal liver during pregnancy²⁶.

Surprisingly, swertiamarin therapy reversed all of the deleterious effects of cytarabine in rats. Swertiamarin, a secoiridoid glycoside derived from the medicinal plant Enicostemma axillare (Lam.), has long been used as an anti-inflammatory²⁰, antioxidant¹³, digestive aid, laxative, liver tonic, anti-malarial, antipyretic, hypoglycemic, and anticancer agent. When given orally for 8 days at dosages of 100 and 200 mg/kg body weight in the presence of the hepatotoxic d-GalN, swertiamarin shows considerable antioxidant and hepatoprotective effects²⁷. Swertiamarin was also reported with cardioprotective effect on rats with experimentally induced myocardial infarction^28,29. This effect may be attributed to the compound's antioxidant activity. However, longer-term, more scientifically credible investigations are necessary to adapt these findings to a therapeutic setting. Furthermore, molecular level investigations are necessary to evaluate Ara-C-induced hepatotoxicity and the protection provided by ST against Ara-C-induced maternal hepatotoxicity.

CONCLUSION:

The current study found that cytarabine can badly injure pregnant rat liver tissues and that swertiamarin can help to partially reverse their liver damage. As a result, swertiamarin may be useful in avoiding cytarabine-induced liver damage. The antioxidant activities of swertiamarin may be primarily responsible for its favorable effects on liver indicators. More research is needed to determine its specific method of action.

ACKNOWLEDGMENT:

We are grateful to the administration of JSS College of Pharmacy for providing the research facilities needed to complete the current work.

AUTHORS’ CONTRIBUTIONS:

All the authors contributed equally in design and frame of the work, acquisition and interpretation of data and manuscript preparation, all authors have read the prepared manuscript and approved for the publication.

CONFLICT OF INTEREST:

No conflict of interest from all the authors.

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Received on 05.11.2022 Modified on 07.04.2023

Research J. Pharm. and Tech 2023; 16(12):5707-5712.

DOI: 10.52711/0974-360X.2023.00923