# The Rhizome of Curculigo pilosa Exerts Hepatoprotective and Nephroprotective Effects in Rats Exposed to Acetaminophen Toxicity

O O Ogunrinola, O K Awote, O A Ogunrinola, H A Popoola, G O Ajetunmobi, C A Mbahokafor

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O O Ogunrinola, O K Awote, O A Ogunrinola, H A Popoola, G O Ajetunmobi, et al.. The Rhizome of Curculigo pilosa Exerts Hepatoprotective and Nephroprotective Effects in Rats Exposed to Acetaminophen Toxicity. South Asian Research Journal of Natural Products, 2023, 5 (4), pp.9-15. hal-04020143

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# The Rhizome of *Curculigo pilosa* Exerts Hepatoprotective and Nephroprotective Effects in Rats Exposed to Acetaminophen Toxicity

O. O. Ogunrinola<sup>a*</sup>, O. K. Awote<sup>a</sup>, O. A. Ogunrinola<sup>a,b</sup>, H. A. Popoola<sup>a</sup>, G. O. Ajetunmobi<sup>a</sup>, D. O. Moshood<sup>a</sup> and C. A. Mbahokafor<sup>a</sup>

## Authors' contributions

This work was carried out in collaboration among all authors. Author OOO designed the study, performed the statistical analysis, wrote the protocol. Author HAP, GOA, DOM and CAM managed the analyses of the study. Author OAO managed the analysis of data. Author OOO, OKA and OAO managed the literature searches and wrote the manuscript. All authors read and approved the final manuscript.

## Article Information

### Open Peer Review History:

This journal follows the Advanced Open Peer Review policy. Identity of the Reviewers, Editor(s) and additional Reviewers, peer review comments, different versions of the manuscript, comments of the editors, etc are available here: https://www.sdiarticle5.com/review-history/97213

### Original Research Article

Received 25 October 2022

Accepted 29 December 2022

Published 30 December 2022

## ABSTRACT

**Aims:** The exposition of drug-induced hepatotoxicity and nephron injury is highly uneven; some range from asymptomatic but elevated liver and kidney parameters to meteoric liver and kidney damage. The medicinal plants have been exploited for fighting toxicity, but their mechanisms remain unexplored. The purpose of this study was to see how an aqueous extracts of *Curculigo pilosa* (*C. pilosa*) rhizome affected the hepato- and nephro-toxicity caused by 750 mg/kg and 1000 kg/mg body weight doses of acetaminophen (APAP) in rats.

**Methodology:** Thirty (30) female rats used for this study were divided into six groups (n = 5). Group A served as control. *C. pilosa* (300 mg/kg body weight) was given to Group B. Group C was administered a 750 mg/kg body weight dose of APAP. Group D was administered a 750 mg/kg body weight APAP dose plus 300 mg/kg body weight of an aqueous extracts of *C. pilosa*. A 1000 mg/kg body weight APAP dose was given to Group E. Group F was administered APAP (dose 1000 mg/kg body weight) plus an aqueous extracts of *C. pilosa* (300 mg/kg body weight). The

<footnote><sup>a</sup> Department of Biochemistry, Faculty of Science, Lagos State University, Ojo, Lagos State, Nigeria.</footnote>

<footnote><sup>b</sup> School of Nutrition Sciences, Faculty of Health Sciences, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada.</footnote>

<footnote>*Corresponding author: Email: olabisi.ogunrinola@lasu.edu.ng, ooogunrinola@yahoo.com;</footnote>
serum concentrations of urea, creatinine, chloride, potassium, sodium, alanine transaminase (ALT), aspartate transaminase (AST), and alkaline phosphatase (ALP) were analyzed using standard methods.

**Results:** The APAP-induced toxicity caused a significant (*P*=.05) increase in the levels of ALT, AST, ALP, creatinine, urea, potassium, sodium, and chloride, but treatment with an aqueous extracts of *C. pilosa* rhizome significantly (*P*.=05) decreased the levels of these markers compared to the control.

**Conclusion:** The aqueous extracts of *C. pilosa* rhizome has hepatoprotective and nephroprotective effects against APAP-induced toxicity.

Keywords: Hepatoprotective; nephrotoxicity; acetaminophen; Curculigo pilosa.

# 1. INTRODUCTION

The naturally occurring phytoconstituents compounds (alkaloids, phenols, saponins, carbohydrates, terpenoids, steroids, flavonoids, and tannins, among others) in plants are derived from different plant parts and are primarily responsible for the treatment of different illnesses and diseases brought on by toxicity [1]. Acetamionophen (APAP) causes hepatotoxicity and nephrotoxicity. APAP is commonly used as an analgesic and antipyretic drug to relieve mild and chronic pain and reduce fever when taken in a normal, prescribed dose. Its metabolism happens within liver microsomes, where it forms water by conjugating with glucuronate and sulfate to be eliminated from the liver and blood through the bile and urine [2-4]. At prescribed doses, APAP is oxidized to the electrophile N-acetyl-p-benzoquinone imine (NAPQI), a toxic compound, by microsomal cytochrome P450. The detoxification of NAPQI is done with reduced glutathione (GSH) by conjugation to form the acetaminophen-glutathione conjugate (APAP-SG). The prolonged use of APAP causes APAP-SG, which, collectively with GSH depletion, stirs up a series of damaging reactions leading to acute liver damage (ALD) and cell death [2,4]. In addition to ALD, the long-term use of APAP is metabolized in the kidney to produce NAPQI that is deacetylated to produce a nephrotoxic product, 4-aminophenol (PAP), resulting in nephrotoxicity such as acute kidney injury (AKI). The APAP-induced toxicity results in oxidative stress, inflammation, lipid peroxidation, protein oxidation, modification and inhibition of enzyme activity, mitochondrial dysfunction, and endoplasmic reticulum stress [2,3,5-7].

The search for a drug with hepato-nephro-protective and/or hepato-nephro-regenerative functions that is reliable, without side effects, and readily available is difficult [8,9]. *Curculigo pilosa* (*C. pilosa*) is a tuberous rhizome herb belonging

to the Amaryllidaceae family, widely distributed in the tropical West Africa, and, known as “epakun” in the Yoruba traditional medicine of southwestern Nigeria. It is used in the treatment of hernia, infertility, genital infections, sexually transmitted infections, etc. [10,11]. In addition it is used in the production of baby food and sorghum beer in West Africa [12]. The mechanism of action in carrying out these treatments remains enigmatic. The present study is designed to investigate the hepatoprotective and nephroprotective properties of APAP in toxicity-induced rats.

# 2. METHODOLOGY

## 2.1 Plant Collection and Extraction

*C. pilosa* rhizomes were purchased from a Lusada market, Ado-odo/ota L.G.A., Ogun State, in South Western part of Nigeria, and identified by the Department of Botany, Lagos State University, Ojo, Lagos State, Nigeria. The rhizomes were thoroughly washed under clean running water and grounded with high speed blender (Kenwood BLK - 828), and 200 g were boiled in 1000 ml of clean water for 30 minutes. The solution was filtered using Whatman's No.1 filter paper, and the filtrate was concentrated using a rotary evaporator. The extract was kept in the refrigerator prior to analysis (4°C). The dried mass yielded 62.5 g.

## 2.2 Experimental Animals

Thirty (30) healthy female Wistar rats weighing 85-100 g were kept in the animal house of the Department of Biochemistry, Lagos State University, Ojo, Lagos, Nigeria, between April 2018 and July 2018. The animals were acclimatized for two (2) weeks, fed *ad libitum* daily with commercial rat feed (product of Animal care, Lagos, Nigeria), and clean water, and kept under a constant 12-hour light and dark cycle. A
single dose of acetaminophen suspension was
administered by the oral route, at a dose of 750
mg/kg b.wt (groups C - D) and 1000 mg/kg b.wt
edi (groups E - F). Preliminary pilot studies showed
that aqeous C. pilosa extracts was not toxic up to
300mg/kg body weight, according to the method
of Karigidi and Olaiya [13]. The experimental
protocols were conducted in accordance with the
international guiding principles of laboratory
animal care [14] and were approved by the
Animal Ethical Committee of the Department of
Biochemistry, Lagos State University; Ojo,
Nigeria.

2.3 Experimental Design

The rats were randomly divided into six (6)
groups of five rats each as shown below:

Group A = Control

Group B = Rats treated with 300 mg/kg body
weight of C. pilosa aqueous extracts

Group C = Rats treated with 750 mg/kg body
weight acetaminophen

Group D = Rats treated with 750 mg/kg body
weight acetaminophen plus 300 mg/ kg body
weight of C. pilosa aqueous extracts

Group E = Rats treated with 1000 mg/kg body
weight acetaminophen

Group F = Rats treated with 1000 mg/kg body
weight acetaminophen plus 300 mg/ kg body
weight of C. pilosa aqueous extracts

The extracts were administered orally for 14 days
using intragastric tube. After 14 days, the rats
were fasted overnight and euthanized under light
anesthesia. The blood was collected without
anticoagulant sample bottles for serum.

## 2.4 Blood Sample Collection and Biochemical Analysis

Blood samples for biochemical analysis were
collected from all the rats under light ether
anaesthesia by cardiac puncture with a syringe
into plain tubes and allowed to clot. Serum was
separated with a high speed macro-centrifuge at
3,500 rpm for 10 minutes and stored for further
analysis. The activities of aspartate
aminotransferase (AST), alanine
aminotransferase (ALT), and alkaline
phosphatase (ALP) were examined with
commercial diagnostic kits (Randox Laboratories

Ltd. UK) according to the description by
Ogunrinola et al. [15] and Afolabi et al. [16]. The
concentrations of urea, and creatinine were
analysed in the serum using commercial kits
(Agappe Diagnostics, Switzerland), as reported
by Afolabi et al. [16], while the electrolytes
(sodium, potassium, and chloride) were
determined in the serum using commercial kits
(Agappe Diagnostics, Switzerland), as previously
reported by Obetan et al. [17]. All these analyses
were performed using a colorimetric instrument
from Surgienfield Instrument, Zhejiang, China,
Mainland.

2.5 Statistical Analysis

Data were expressed as mean ± SEM, and
analyzed by one-way analysis of variance
(ANOVA) using Statistical Package for Social
Sciences version 17.0 (SPSS, Chicago, Illinois).
Values that gave a p <0.05 were taken to be
statistically significant.

3. RESULTS AND DISCUSSION

The variables that were assessed in the current
investigation, including creatinine, urea, chloride,
potassium, sodium, alanine transaminase (ALT),
aspartate transaminase (AST), and alkaline
phosphatase (ALP) concentrations, provided an
indirect evaluation of hepatic and renal function.
In the liver, ammonia, a waste product and highly
toxic substance, is detoxified through conversion
to urea, which is nontoxic and water-soluble and
excreted through urine by the kidneys, but a high
concentration of urea is also toxic, hence it is
considered a marker of hepatic or renal
functional status [18,19]. Likewise, creatinine is
an excretion product of muscle activity, and its
elimination is entirely by the kidneys, where it is
freely filtered in renal glomeruli, by the tubular
component, which is a good indicator of renal-
glomerular function [19]. The kidney's capacity to
control blood volume and chemical composition
in accordance with the body's shifting needs calls
for a very sophisticated functional system. Renal
functions are coordinated with those of the
cardiovascular and pulmonary systems to
maintain homeostasis to a significant extent [17].
Both urea and creatinine are end products of
body metabolism and essentially reflect the
glomerular filtration rate (GFR) [18,20]. APAP-
induced hepatotoxicity and nephron injury are
usually characterized by elevated serum levels of
urea and creatinine, which are significant
biomarkers of renal dysfunction [20,21]. In the
present study, urea and creatinine
concentrations, as indicated in Table 1, were elevated in APAP-treated rats (750 and 1000 mg/kg b.wt), respectively, suggesting kidney damage compared to the control (0.56±0.15 mg/ml (creatinine); 25.74±2.64 mg/ml (urea)) and *C. pilosa* extracts (0.47±0.11 mg/ml (creatinine); 23.71±1.41 mg/ml (urea)) groups. This is in accordance with the administration of acrylamide [19], and lipopolysaccharide [6], respectively. The treatment with an aqueous extracts of *C. pilosa* rhizome the APAP-induced toxicity significantly (P= .05). This indicates that the aqueous extracts of *C. pilosa* ameliorate renal damage. It may be due to the phytoconstituents present in the *C. pilosa* aqueous extracts that inhibit the accumulation of urea and creatinine, respectively. This is in agreement with the research of Imo and Uhegbu [22], and Karigidi and Olaiya [13].

Overdose of APAP causes similar tubular effects to non-steroidal anti-inflammatory drugs via inhibition of prostaglandin synthesis, vasoconstriction, and activation of the renin-angiotensin-aldosterone system, causing electrolyte changes and/or disturbances [23]. The stability of the blood's sodium, potassium, and chloride contents is a reliable sign of how well the kidneys and heart are working. An increase in electrolytes (potassium, sodium, and chloride) is the hallmark of APAP-induced toxicity. The serum electrolytes, potassium (K+), sodium (Na+), and chloride (Cl-), are presented in Table 2. It was observed that, in the APAP-induced groups, there is a significant (P= .05) increase in the concentration of K+, Na+, and Cl- compared to the control (3.69±0.25 mEg/L (K+); 133.17±2.66mEg/L (Na+), 73.13±6.98 mEg/L (Cl-)) and *C. pilosa* extracts (3.24±0.26 mEg/L (K+); 130.10±3.94 mEg/L (Na+), 72.79±7.15 mEg/L (Cl-)) groups. The intoxication of APAP leads to the breakdown of endogenous tissue and as a result, the derangement of serum electrolytes that occurs [24]. Toxic and overdose of APAP induces nephron damage, forms serum osmolality of the electrolytes (K+, Na+, and Cl-), and significantly (P= .05) elevates these parameters, which may be due to renal hemodynamic compromise and tubular dysfunction [25,26]. The administration of an aqueous rhizome extracts of *C. pilosa* significantly decreased the electrolytes, thereby protecting any of the alterations. This is in accordance with the research of Imo and Uhegbu [22]. A decrease in sodium lowers blood

pressure in hypertensive individuals because there is linked between sodium and blood pressure. Likewise, potassium in the intracellular fluid, has been reported to be among the protective electrolytes against hypertension. The decrease effect of aqueous rhizome extracts of *C. pilosa*, is an indication that membrane structure may possibly be protected or stabilized, as observed with *Gongronema latifolium* Benth leaf extracts by Imo and Uhegbu [22].

The liver is the vital organ that is highly sensitive to toxic agents, and its functions include detoxification of deleterious materials, regulation of numerous metabolic processes, and maintenance of body homeostasis [27,28]. The elevation of serum hepatic biomarker enzymes (ALT, AST, and ALP) is an indication of hepatocellular damage, which reveals liver enzyme leakage into the blood stream and loss of functional integrity of cell membrane in liver [8,29-31]. ALP level in the serum is a mark of liver function or bone metabolism due to its involvement in the transport of metabolites across the cell membranes, glycogen metabolism, secretory activities, and protein synthesis [15]. The increase in serum ALP level is caused by increased synthesis in the presence of increasing biliary pressure because serum ALP is connected to hepatic cell function [28]. Being a sensitive sign of liver disease, AST is in charge of transaminating aspartate in the body's metabolism, whereas ALT, which is found in hepatocytes, is released into the blood during the cell damage [15]. The results in Table 3 showed a significant (P= .05) increase in ALT, AST, and ALP liver enzymes in the APAP-induced groups compared to the control (29.64±2.59 U/L (ALT); 37.00±1.09 U/L (AST),23.88±0.26 U/L (ALP)) and *C. pilosa* extracts (25.75±0.71 U/L (ALT); 30.56±0.98 U/L U/L (AST), 21.981±0.68 U/L (ALP)) groups. This causes liver damage as a result of the leakage of these hepatic enzymes into the circulation. These liver enzyme concentrations were significantly (p<0.05) lower in the *C. pilosa* aqueous extracts-treated groups. The report confirms previous findings by Ogunrinola et al. [15], and Lakshmi et al. [24]. The reversal of these enzymes with *C. pilosa* aqueous extracts is evidence of the protection of cellular membrane integrity and tissue damage against APAP-induced damage, which may be due to the presence of the phytoconstituents by preventing oxidation [15,32-34].
<table><caption>**Table 1. Effects of *C. pilosa* aqueous extracts on kidney functions of acetaminophen-induced toxicity**</caption><thead><tr><th>Treatment dose</th><th>Creatinine Conc. (mg/ml)</th><th>Urea Conc. (mg/ml)</th></tr></thead><tbody><tr><td>Control</td><td>0.56±0.15<sup>a</sup></td><td>25.74±2.64<sup>a</sup></td></tr><tr><td><i>C. pilosa</i> (300 ml/kg b. wt) aq. extr.</td><td>0.47±0.11<sup>b</sup></td><td>23.71±1.41<sup>b</sup></td></tr><tr><td>750 mg/kg b. wt APAP</td><td>2.86±0.05<sup>c</sup></td><td>60.97±7.07<sup>c</sup></td></tr><tr><td>750 mg/kg b.wt APAP + <i>C. pilosa</i> (300 ml/kg b. wt) aq. extr.</td><td>1.29±0.22<sup>d</sup></td><td>33.92±4.28<sup>d</sup></td></tr><tr><td>1000 mg/kg b.wt APAP</td><td>3.02±0.29<sup>e</sup></td><td>65.10±2.31<sup>e</sup></td></tr><tr><td>1000 mg/kg b.wt APAP+ <i>C. pilosa</i> (300 ml/kg b. wt) aq. extr.</td><td>1.42±0.31<sup>f</sup></td><td>37.14±4.86<sup>f</sup></td></tr></tbody></table>

Values are represented as Mean values ± Standard error of means, n=5. Rows of the same compartment carrying different letters of the alphabet are significantly different from each other (P=.05). APAP = acetaminophen (paracetamol), b. wt = body weight, aq. extr. = aqueous extracts, Conc.= concentration

<table><caption>**Table 2. Effects of *C. pilosa* aqueous extracts on serum electrolytes of acetaminophen-induced toxicity**</caption><thead><tr><th>Treatment dose</th><th>Potassium Conc. (mEg/L)</th><th>Sodium Conc. (mEg/L)</th><th>Chloride Conc. (mEq/L)</th></tr></thead><tbody><tr><td>Control</td><td>3.69±0.25<sup>a</sup></td><td>133.17±2.66<sup>a</sup></td><td>073.13±6.98<sup>a</sup></td></tr><tr><td><i>C. pilosa</i> (300 ml/kg b. wt) aq. extr.</td><td>3.24±0.26<sup>b</sup></td><td>130.10±3.94<sup>b</sup></td><td>072.79±7.15<sup>b</sup></td></tr><tr><td>750 mg/kg b.wt APAP</td><td>6.61±0.71<sup>c</sup></td><td>150.96±2.39<sup>c</sup></td><td>117.61±2.73<sup>c</sup></td></tr><tr><td>750 mg/kg b.wt APAP + <i>C. pilosa</i> (300 ml/kg b. wt) aq. extr.</td><td>5.47±0.35<sup>d</sup></td><td>143.89±4.93<sup>d</sup></td><td>083.67±6.14<sup>d</sup></td></tr><tr><td>1000 mg/kg b.wt APAP</td><td>7.74±0.25<sup>e</sup></td><td>157.29±1.94<sup>e</sup></td><td>140.12±3.65<sup>e</sup></td></tr><tr><td>1000 mg/kg b.wt APAP + <i>C. pilosa</i> (300 ml/kg b. wt) aq. extr.</td><td>6.32±0.49<sup>f</sup></td><td>138.15±0.59<sup>f</sup></td><td>129.72±2.14<sup>f</sup></td></tr></tbody></table>

Values are represented as Mean values ± Standard error of means, n=5. Rows of the same compartment carrying different letters of the alphabet are significantly different from each other (P=.05). APAP = acetaminophen (paracetamol), b. wt = body weight, aq. extr. = aqueous extracts, Conc.= concentration

<table><caption>**Table 3. Effects of *C. pilosa* aqueous extracts on liver function test biomarkers of acetaminophen-induced toxicity**</caption><thead><tr><th>Treatment dose</th><th>Alanine transaminase Conc. (U/L)</th><th>Aspartate transaminase Conc. (U/L)</th><th>Alkaline phosphatase Conc. (U/L)</th></tr></thead><tbody><tr><td>Control</td><td>29.64±2.59<sup>a</sup></td><td>37.00±1.09<sup>a</sup></td><td>23.88±0.26<sup>a</sup></td></tr><tr><td><i>C. pilosa</i> (300 ml/kg b. wt) aq. extr.</td><td>25.75±0.71<sup>b</sup></td><td>30.56±0.98<sup>b</sup></td><td>21.981±0.68<sup>b</sup></td></tr><tr><td>750mg/kg b.wt APAP</td><td>59.45±2.51<sup>c</sup></td><td>49.04±1.21<sup>c</sup></td><td>21.50±0.47<sup>c</sup></td></tr><tr><td>750mg/kg b.wt APAP + <i>C. pilosa</i> (300 ml/kg b. wt) aq. extr.</td><td>50.59±2.49<sup>d</sup></td><td>25.44±1.87<sup>d</sup></td><td>18.39±0.39<sup>d</sup></td></tr><tr><td>1000mg/kg b.wt APAP</td><td>82.42±2.35<sup>e</sup></td><td>74.50±1.79<sup>e</sup></td><td>25.68±0.42<sup>e</sup></td></tr><tr><td>1000mg/kg b.wt APAP + <i>C. pilosa</i> (300 ml/kg b. wt) aq. extr.</td><td>64.04±3.46<sup>f</sup></td><td>62.18±2.17<sup>f</sup></td><td>23.91±0.22<sup>f</sup></td></tr></tbody></table>

Values are represented as Mean values ± Standard error of means, n=5. Rows of the same compartment carrying different letters of the alphabet are significantly different from each other (P=.05). APAP = acetaminophen (paracetamol), b. wt = body weight, aq. extr. = aqueous extracts, Conc.= concentration

**4. CONCLUSION**

According to this study, the oral administration of *C. pilosa* aqueous extracts recovered the liver from hepatotoxicity and the kidney from nephrotoxicity. The protective effect of the extract may be due to the presence of bioactive compounds that lead to hepatoregenerative and nephroprotective capacities. Further studies are needed to investigate the molecular targets

involved in the hepatoregenerative and nephroprotective effects. The current study only looked at the effect of *C. pilosa* aqueous extracts on the APAP hepato-and nephro-toxicity maker parameters; however, more research into the mechanism of action of APAP on membrane integrity and stress on other body organs, as well as the effects of *C. pilosa* aqueous extracts is needed.
## ETHICAL APPROVAL

All authors hereby declare that the Guide for the Care and Use of Laboratory Animals, "NIH Publication No. 85-23," Revised 1985, was followed, as well as specific national laws where applicable. All experiments have been examined and approved by the appropriate ethics committee.

## COMPETING INTERESTS

Authors have declared that no competing interests exist.

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