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 Table of Contents  
ORIGINAL ARTICLE
Year : 2022  |  Volume : 10  |  Issue : 3  |  Page : 74-80

Dexamethasone-induced derangement in some liver function parameters: Hepatoprotective effect of L-Citrulline


1 Department of Human Physiology, Kaduna State University, Kaduna, Nigeria
2 Department of Human Physiology, Ahmadu Bello University, Zaria, Kaduna State, Nigeria

Date of Submission23-Aug-2022
Date of Decision10-Sep-2022
Date of Acceptance13-Sep-2022
Date of Web Publication05-Dec-2022

Correspondence Address:
Dr. Timothy Danboyi
Department of Human Physiology, Kaduna State University, Kaduna, Kaduna State
Nigeria
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/njecp.njecp_11_22

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  Abstract 

Background: Dexamethasone is not only a potent glucocorticoid with several health benefits but is also associated with severe side effects, one of which is hepatotoxicity. L-Citrulline is known to possess antioxidant, antidiabetic, and antidyslipidemic effects, among others, of which hepatoprotection has not been extensively explored. We aimed to assess the effect of L-Citrulline on dexamethasone-induced derangement in liver enzymes and serum proteins in Wistar rats. Materials and Methods: Twenty-five male Wistar rats, weighing between 200 and 250 g, were randomly assigned into five groups of five rats each. While Group I received no intervention, dexamethasone intraperitoneally (1 mg/kg) was administered to the other groups for 7 days. Groups III, IV, and V were pretreated with 200, 400, and 800 mg/kg L-Citrulline daily for 21 days, respectively. Biochemical assessment was made after humanely sacrificing the animals. Values at P < 0.05 were considered statistically significant compared to the dexamethasone group. Results: L-Citrulline significantly lowered the levels of aspartate transferase (AST), alanine transferase (ALT), gamma–glutamyltransferase, and serum total and conjugated bilirubin in a dose-dependent manner. The greatest reduction in alkaline phosphatase level by L-Citrulline was recorded at 200 mg/kg (13.96 ± 0.73 IU/L). Similarly, the total protein level was significantly increased by L-Citrulline 800 mg/kg (9.38 ± 0.39 g/dL), but the greatest increase in albumin level was at 400 mg/kg (4.20 ± 0.21 g/dL). In a dose-dependent manner, the AST: ALT ratios were markedly reduced while the albumin: globulin ratios were greatly increased following L-Citrulline supplementation. Conclusion: L-Citrulline supplementation confers hepatoprotective effect against dexamethasone-induced derangements in liver enzymes and serum proteins in Wistar rats.

Keywords: Dexamethasone, hepatoprotective, hepatotoxicity, L-Citrulline, liver enzymes, serum proteins


How to cite this article:
Danboyi T, Jimoh A, Hassan-Danboyi E, Alhassan AW, Dubo AB. Dexamethasone-induced derangement in some liver function parameters: Hepatoprotective effect of L-Citrulline. Niger J Exp Clin Biosci 2022;10:74-80

How to cite this URL:
Danboyi T, Jimoh A, Hassan-Danboyi E, Alhassan AW, Dubo AB. Dexamethasone-induced derangement in some liver function parameters: Hepatoprotective effect of L-Citrulline. Niger J Exp Clin Biosci [serial online] 2022 [cited 2023 Feb 9];10:74-80. Available from: https://www.njecbonline.org/text.asp?2022/10/3/74/362645


  Introduction Top


Hepatotoxicity is the most common reason why medications are withdrawn from the market.[1],[2],[3] Drug-induced hepatotoxicity accounts for 5% of all hospital admissions[4] and about 20%–40% of all fulminant hepatic failure.[5] It is a potential complication of virtually any drug due to the liver's role in drug metabolism and excretion.[6],[7] The liver aminotransferases enzymes, alanine transferase (ALT), aspartate transferase (AST), and alkaline phosphatase (ALP) levels are often elevated in acute liver injury as seen in drug overdose,[8] but AST is not specific to the liver, at such elevated level of AST may not be a marker of liver damage.[9]

Glucocorticoids (GCs) are naturally occurring steroid hormones (e.g., cortisol and corticosterone) produced in response to stressful conditions. Exogenous GCs such as dexamethasone are also available and are used in the prevention and treatment of several disease conditions such as rheumatoid arthritis, severe allergies, and adrenocortical insufficiency. Dexamethasone is a potent diabetogenic drug that increases whole-body insulin resistance and plasma glucose level leading to the development of diabetes mellitus.[10],[11],[12],[13] It has anti-inflammatory and immunosuppressant actions as a powerful synthetic adrenocorticoid.[12] Some studies have reported dexamethasone to be hepatoprotective at normal doses in sheep and goats[14] and in rats,[15],[16] but its effect even at low doses and over a long period is now known to be adverse and severe.[17]

The adverse effect of prolonged dexamethasone therapy is well documented, including hyperglycemia, dyslipidemia, steatosis, lipid peroxidation, and hematological derangements.[17],[18],[19] Moreover, cases of drug-induced liver injuries had also been reported with other GCs, such as methylprednisolone.[20]

L-Citrulline, which is synthesized in the liver is known to play a role in the metabolism of nitric oxide[21],[22] and prevents its excessive and uncontrolled production.[23] L-Citrulline also plays a role in the treatment and prevention of cardiovascular diseases or events.[24],[25],[26] In our previous study,[19] we demonstrated that L-Citrulline possesses antidiabetic and antidyslipidemic properties. There are evidence that L-Citrulline possesses antioxidant effects.[27],[28]

However, to the best of our knowledge, the hepatotoxicity associated with dexamethasone administration and the potential protection that could be provided by L-Citrulline supplementation have not been explored before. It was necessary to carry out this study citing the increasing cases of drug-induced hepatotoxicity (especially dexamethasone-induced toxicity) and the availability of the main natural source of L-Citrulline (watermelon) in this environment. It was expected that L-Citrulline could protective the liver against dexamethasone-induced injury. Hence, this study aimed to investigate the derangement in liver enzymes and serum proteins associated with dexamethasone administration and the hepatoprotective effect offered by L-Citrulline.


  Materials and Methods Top


Materials

Dexamethasone and L-Citrulline were purchased from MedChem Xpress (United States of America). Reagents used were commercially obtained from reputable pharmaceutical companies and of analytical grade. Other materials used include disposable syringes and gloves, distilled water, electronic weighing balance, sample bottles, dissecting kit and board, centrifuge, and marker.

Experimental animals

Twenty-five male Wistar rats (Rattus norvegicus), weighing 200–250 g were obtained from the animal house of the Human Physiology Department, Ahmadu Bello University (A.B.U), Zaria. They were given free access to commercial grower mash feed (rat chow) and water. Their houses are plastic cages with iron mesh as roof and sawdust bedding as floor. Their water was changed daily while the floor bedding was changed every other day. Standard laboratory conditions were ensured throughout the experiment.

Ethical approval

This study was approved by the Ethical Committee on Research Animals' Use and Care, A.B.U, Zaria (Approval Number: ABUCAUC/2020/72), and it was carried out based on their guidelines for the use of animals in research.[29]

Experimental animal grouping

Twenty-five rats were randomly assigned into five groups of five rats each and were given:

Group I (n=5): no intervention was given to this group. They served as the normal control.

Group II (n=5): an intraperitoneal (i.p.) injection of dexamethasone 1 mg/kg body weight daily for 7 days.[29]

Group III (n=5): L-citrulline 200 mg/kg body weight daily for 21 days plus i.p. dexamethasone 1 mg/kg body weight daily for 7 days starting from day 15 of L-citrulline treatment.[19]

Group IV (n=5): L-citrulline 400 mg/kg body weight daily for 21 days plus i.p. dexamethasone 1 mg/kg body weight daily for 7 days starting from day 15 of L-citrulline treatment.[19]

Group V (n=5): L-citrulline 800 mg/kg body weight daily for 21 days plus i.p. dexamethasone 1 mg/kg body weight daily for 7 days starting from day 15 of L-citrulline treatment.[19]

Blood collection

The rats were anesthetized with 75 mg/kg ketamine and 5 mg/kg diazepam (i.p.). About 4 ml of blood was drawn from each rat through cardiac puncture. Blood collected was allowed to stand in the plain tubes and clot for 30 min; the resulting samples were centrifuged at 3000 rpm for 10 min. Centrifuged samples were kept at a temperature approximately between −2°C and −10°C) until analysis.

Determination of serum liver enzymes, bilirubin, and protein levels

Assessment of liver enzymes (AST, ALT, ALP, and gamma-glutamyltransferase [GGT]) was done using commercially available diagnostic kits (BioAssay Systems, Hayward, CA, USA), according to the manufacturers' guidelines. Serum liver enzymes level of activity was expressed as IU/L.

Serum total and conjugated bilirubin were assessed based on the van den Bergh reaction, which is in two phases.[30] The first was the assessment of the water-soluble conjugated fraction directly. This was seen as an emission of purple light on reacting with diazo reagent (sulfanilic acid and sodium nitrate in HCl). The second was the measurement of the total bilirubin level by the addition of methyl alcohol, which dissolves the insoluble unconjugated fraction.

The modified Biuret method was used to assess the total protein. This is based on the production of violet color when protein reacts with copper sulfate (a component of the Biuret reagent) in an alkaline medium.[31],[32] The serum albumin was assessed using a bromocresol green, with which it forms a complex, and the absorbance was determined at a wavelength of 596 nm. The serum globulin was then obtained from the difference between total protein and albumin levels. It was expressed in g/dL.


  Results Top


Effects of dexamethasone on liver enzymes and serum protein levels in male Wistar rats

Results in [Table 1] showed that dexamethasone caused significant elevations (P < 0.001) in all the liver enzymes (AST [193.20 ± 6.08 IU/L], ALT [57.40 ± 0.93 IU/L], ALP [26.18 ± 1.75 IU/L] and GGT [16.91 ± 2.91 IU/L]) and serum total (3.28 ± 0.83 mg/dL) and conjugated (1.96 ± 0.74 mg/dL) bilirubin levels compared to the normal control. Even the serum total protein (7.38 ± 0.18 g/dL) and albumin (1.78 ± 0.09 g/dL) levels were markedly reduced (P < 0.01) by dexamethasone administration compared to the normal control [Table 2].
Table 1: Effect of L-citrulline on level of liver enzymes in dexamethasone-induced hepatotoxicity in male Wistar rats

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Table 2: Effect of L-citrulline on serum protein levels in dexamethasone-induced hepatotoxicity in male Wistar rats

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Effects on L-Citrulline on liver enzymes in dexamethasone-induced hepatotoxicity in male Wistar rats

Compared to the dexamethasone group, L-Citrulline was able to reduce the levels of activities of AST, ALT, GGT, and total and conjugated bilirubin levels in a dose-dependent pattern at P < 0.01 [Table 1]. However, the most significant effect (P = 0.0001) of L-Citrulline on ALP level was observed at 200 mg/kg (13.96 ± 0.73 IU/L) and the least at 800 mg/kg (21.04 ± 0.62 IU/L) compared to the dexamethasone group (26.18 ± 1.75 IU/L).

Total bilirubin levels were drastically reduced by L-Citrulline in a dose-dependent manner (2.09 ± 0.39, 2.00 ± 0.18, and 1.24 ± 0.20 mg/dL at 200, 400, and 800 mg/kg, respectively) compared to dexamethasone (3.28 ± 0.83 mg/dL) at P = 0.002. In the same manner, the level of the conjugated bilirubin was also lowered correspondingly at P = 0.000 [Table 1].

Dexamethasone showed a much higher AST: ALT ratio (3.31 ± 0.05) when compared to the normal control (2.82 ± 0.04). This ratio was significantly (P = 0.002) decreased by L-Citrulline in a dose-dependent manner, most especially at 800 mg/dL (1.19 ± 0.02) [Figure 1].
Figure 1: Effect of L-Citrulline on AST: ALT ratio in dexamethasone-induced hepatotoxicity in male Wistar rats. Superscripts a, b, c, and d denote significant differences compared to normal control, dexamethasone, CIT 200, and CIT 400 groups, respectively. One-way ANOVA, followed by Tukey's post-hoc test, was carried out. NC: Normal control, Dexa: Dexamethasone, CIT: L-Citrulline, ALT: Alanine aminotransferase, AST: Aspartate aminotransferase, A: Albumin, G: Globulin. ANOVA: Analysis of variance

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Effects on L-Citrulline on serum protein level in dexamethasone-induced hepatotoxicity in Wistar rats

L-Citrulline was able to increase the serum total protein levels at all doses but with a significant effect (P = 0.008) seen at 800 mg/kg dose (9.38 ± 0.39 g/dL) compared to the dexamethasone group (7.38 ± 0.18 g/dL). Similarly, there were increases in the serum albumin levels at all doses of L-Citrulline (3.90 ± 0.14 g/dL at 200 mg/kg; 4.20 ± 0.21 g/dL at 400 mg/kg; and 4.00 ± 0.23 g/dL at 800 mg/kg) compared to the dexamethasone group (1.78 ± 0.09 g/dL) [P < 0.001; [Table 2]].

In [Figure 1], the albumin: globulin (A:G) ratio was significantly (P < 0.001) reduced by dexamethasone (0.30 ± 0.01) compared to the normal control (1.04 ± 0.06), but this was ameliorated by L-Citrulline at all doses, especially at 400 mg/kg (1.36 ± 0.01) (P = 0.0001).


  Discussion Top


In this study, dexamethasone caused a significant elevation of all the liver enzymes (AST, ALT, ALP, and GGT) and serum total and conjugated bilirubin. This is in agreement with previous studies.[17],[18] Although corticosteroids (dexamethasone in particular) are generally safe medications used in the treatment of several ailments, adverse effects such as hepatotoxicity arising from some of them, especially at high doses, have been reported.[17],[18],[19],[20]

The dosage of dexamethasone as well as the duration of administration may be the major factors determining its hepatoprotective or toxic effect. The dosage employed in this study was higher than that used in most studies,[14],[33],[34] which demonstrated it to be protective. On the contrary, a study by Abo-Youssef and Messiha[35] showed significant hepatoprotection (decrease AST and ALT levels, as well as biomarkers of oxidative stress and inflammation) by dexamethasone at 5 mg/kg (a dose higher than ours) in rats exposed to ischemic/reperfusion injury. Nevertheless, it was a pretreatment with dexamethasone for a relatively shorter period (3 days) than that employed in the present study. In line with our finding, Jackson et al.[36] reported elevations in both AST and ALT levels following administration of dexamethasone at 50 mg/kg/day for 4 days. However, the exact mechanism behind dexamethasone's protective effect at low doses or toxic effect at high doses remains unclear.

Elevated ALT level is more specific to liver injury than elevated AST as it is primarily found in abundant in the hepatocytes cytoplasm.[37] Gotama et al.[38] also reported elevated ALT levels greater than that of AST levels following doxorubicin administration. This is contrary to our finding, which showed greater elevation in AST level than in ALT level following dexamethasone administration. A possible reason for this may be that dexamethasone toxicity may be widespread, affecting other tissues and cells apart from the hepatocytes. However, supplementation with L-Citrulline from the present study (especially at 800 mg/kg) was able to bring down the AST level even below the normal control level while that of the ALT level remained above the normal control level. Cai et al.[39] evaluated the effect of L-Citrulline in post-surgical septic rats and found a significant decrease in the AST level but not in the ALT level. They attributed this effect to the antioxidant effect of L-Citrulline through prevention of mitochondrial oxidative damage, as the AST is primarily located in the mitochondria, unlike the ALT. In the same study, L-Citrulline was able to enhance superoxide dismutase activity, inhibit cytokine release as well as decrease nitric oxide (NO) production.[39]

The level of GGT, which is a specific marker of hepatobiliary damage and confirms any elevation of AST or ALT as arising from hepatotoxicity,[37],[38] was also decreased by L-Citrulline from our result. This suggests a potent protective effect of L-Citrulline on the liver against dexamethasone-induced toxicity. This is also in line with the findings of Gotama et al.[38]

In addition, the reduction in the level of AST, ALT, and GGT was dose-dependent, signifying greater hepatoprotective effects of L-Citrulline at higher doses. In a similar study by Gotama et al.,[38] L-Citrulline at 300 and 600 mg/kg significantly decreased the elevated serum AST and ALT levels in doxorubicin-induced hepatotoxicity in rats in a dose-dependent manner. In other studies, elevations of all the serum enzymes (apart from GGT) were significantly ameliorated by L-Citrulline supplementation[40] or watermelon consumption.[41]

In a study by Rajcic et al.,[42] female mice initially fed a high-fat, fructose, and cholesterol diet for 8 weeks, showed elevated levels of AST and ALT as markers of nonalcoholic steatohepatitis. However, supplementation with L-Citrulline over 5 weeks was able to attenuate these and other deleterious effects as a result of intake of such diets. If L-Citrulline could protect against the development and/or progression of liver pathologies such as nonalcoholic fatty liver disease (NAFLD), then it may potentially protect the liver against assaults such as dexamethasone-induced hepatotoxicity.

The main mechanism underlying dexamethasone-induced liver injury is through oxidative stress.[17],[18],[28] Although not measured in the present study, other studies have linked hepatotoxicity to oxidative stress.[16],[43] The findings in this study may also suggest that the hepatoprotective effect of L-Citrulline is probably via its antioxidant property as we previously demonstrated[28] acting through NO production (though not assessed in the present study). NO has been reported to ameliorate oxidative stress by scavenging free radicals, inhibiting cytokine production, and causing sinusoidal vasodilatation.[23],[43]

There were remarkable dose-dependent decreases in serum total and conjugated bilirubin levels by L-Citrulline in this study, compared to the elevated levels recorded in the dexamethasone group. Even though not assessed in the present study, a review by Mancuso et al.[44] reported some antioxidant capability of bilirubin to scavenge reactive nitrogen species, thereby preventing nitrosative stress. However, this might need further investigation. Nevertheless, some studies[22],[23],[28] demonstrated the potent antioxidant properties of L-Citrulline, which can sufficiently counter this possible nitrosative tendency and provide adequate antioxidant cover to the liver.

One of the important functions of the liver, the largest organ of the body is the synthesis of plasma proteins, among which is albumin. Our findings showed some preservation of the serum albumin as well as the total protein levels by L-Citrulline supplementation. The low albumin observed in the dexamethasone group may probably suggest an inflammatory process or liver damage. L-Citrulline prevents the over-activation of the urea cycle (though not explored in this study), hence its supplementation can be an effective therapy by halting the muscle wasting that occurs in catabolic states.[45] This is capable of preserving the total protein level in the body, as seen in this study. According to some studies,[46],[47] L-Citrulline could significantly augment muscle protein synthesis. It is also a potential nutritional therapeutic agent for malnourished patients and the elderly.[47]

In the present study, a high AST:ALT ratio characteristic of acute alcoholic intoxication[48] was noted in the normal control even though no such intervention was given. This was significantly even worse in the dexamethasone group, which might be due to the less elevation in ALT level in comparison to that of AST. In contrast to our finding, a greater elevation of ALT than AST level following short-term (4 days) dexamethasone administration was reported by Jackson et al.[36]

The AST: ALT ratio is not only a marker of NAFLD but also an important predictor of risk for developing several chronic diseases such as prostate cancer (i.e., the higher the ratio the greater the risk) though the association between the ratio and prostate cancer was not significant.[49] Ewid et al.,[50] also demonstrated it as a marker for assessing the severity of chronic heart failure. A high AST:ALT ratio was independently and significantly associated with increased risk of cardiovascular mortality both in Type 2 diabetic patients[51] and in nondiabetic patients.[52] Furthermore, it is a determinant of the risk for developing metabolic syndrome[53] as well as cardiovascular disease[54] in study cohorts. However, L-Citrulline in the present study was able to reduce the AST:ALT ratio significantly and in a dose-dependent manner. At 800 mg/kg, the ratio was much lower than that of the normal control. This supports the high efficacy of L-Citrulline as a hepatoprotective supplement in this study.

On the A:G ratio, there was a significant decrease in dexamethasone which was greatly attenuated by L-Citrulline at all doses. This indicates the conserving property of L-Citrulline not only on muscle protein but also on albumin fraction. The A: G ratio was described as an independent marker for the risk of developing chronic kidney disease (CKD) in a prospective population cohort study,[55] in which lower ratios were associated with adverse outcome in non-CKD participants. The A: G ratio is also a prognostic indicator in other chronic diseases.[56],[57] Although not assessed in this study, chronic inflammation was reported as a possible mechanism underlying low A: G ratios.[58] In another study,[36] a slight increase in the A: G ratio was reported with non-significant alterations in the total protein, A: G levels of rats treated with a high-dose dexamethasone (50 mg/kg) over 4 days.


  Conclusion Top


This study demonstrated that L-Citrulline has a potential hepatoprotective effect on dexamethasone-induced liver toxicity. It prevented the severe depletion of albumin by dexamethasone and preserved the A:G ratio. It also maintained the AST:ALT ratio in the rats. Therefore, it could be beneficial to patients on long-term steroid or potentially hepatotoxic therapy and malnourished patients and those at high risk of cardiovascular and other chronic diseases that may adversely affect the liver. There is a need to explore the effects of dexamethasone at different doses employing different durations of treatment and using different strains of rodents, to ascertain the effective dose at which it is protective or toxic to the liver.

Limitations of the study

This study has some limitations. There are no histological photomicrographs to demonstrate the effects of dexamethasone and L-Citrulline on the liver. Nitric oxide and reactive oxygen/nitrogen species were not assessed, nor any marker of inflammation, which could actually shed more light on the mechanism underlying the toxicity of dexamethasone at the dosage we chose and the protective effects of L-Citrulline. Some kidney function parameters such as serum creatinine, urea, and electrolytes could have also been assessed. Further studies are, therefore, needed to overcome these limitations.

Acknowledgment

We appreciate the efforts of all the laboratory personnel of the Department of Human Physiology, Ahmadu Bello University Zaria, for their contribution to the success of this study.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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