Suaeda vermiculata Aqueous-Ethanolic Extract-Based Mitigation of CCl4-Induced Hepatotoxicity in Rats, and HepG-2 and HepG-2/ADR Cell-Lines-Based Cytotoxicity Evaluations.

Salman A A Mohammed,Hussein M Eldeeb,Riaz A Khan,Abdul-Hamid Emwas,Mohsen S Al-Omar,Hamdoon A Mohammed,Benjamin G Poulson,Mariusz Jaremko,Salim Sioud,Mahmoud Z El-Readi

doi:10.3390/plants9101291

Abstract

Suaeda vermiculata, an edible halophytic plant, used by desert nomads to treat jaundice, was investigated for its hepatoprotective bioactivity and safety profile on its mother liquor aqueous-ethanolic extract. Upon LC-MS (Liquid Chromatography-Mass Spectrometry) analysis, the presence of several constituents including three major flavonoids, namely quercetin, quercetin-3-O-rutinoside, and kaempferol-O-(acetyl)-hexoside-pentoside were confirmed. The aqueous-ethanolic extract, rich in antioxidants, quenched the DPPH (1,1-diphenyl-2-picrylhydrazyl) radicals, and also showed noticeable levels of radical scavenging capacity in ABTS (2,2′-azino-bis-3-ethylbenzthiazoline-6-sulphonic acid) assay. For the hepatoprotective activity confirmation, the male rat groups were fed daily, for 7 days (n = 8/group, p.o.), either carboxyl methylcellulose (CMC) 0.5%, silymarin 200 mg/kg, the aqueous-ethanolic extract of the plant Suaeda vermiculata (100, 250, and 500 mg/kg extract), or quercetin (100 mg/kg) alone, and on day 7 of the administrations, all the animal groups, excluding a naïve (250 mg/kg aqueous-ethanolic extract-fed), and an intact animal group were induced hepatotoxicity by intraperitoneally administering carbon tetrachloride (CCl4). All the animals were sacrificed after 24 h, and aspartate transaminase and alanine transaminase serum levels were observed, which were noted to be significantly decreased for the aqueous-ethanolic extract, silymarin, and quercetin-fed groups in comparison to the CMC-fed group (p < 0.0001). No noticeable adverse effects were observed on the liver, kidney, or heart’s functions of the naïve (250 mg/kg) group. The aqueous-ethanolic extract was found to be safe in the acute toxicity (5 g/kg) test and showed hepatoprotection and safety at higher doses. Further upon, the cytotoxicity testings in HepG-2 and HepG-2/ADR (Adriamycin resistant) cell-lines were also investigated, and the IC50 values were recorded at 56.19 ± 2.55 µg/mL, and 78.40 ± 0.32 µg/mL (p < 0.001, Relative Resistance RR 1.39), respectively, while the doxorubicin (Adriamycin) IC50 values were found to be 1.3 ± 0.064, and 4.77 ± 1.05 µg/mL (p < 0.001, RR 3.67), respectively. The HepG-2/ADR cell-lines when tested in a combination of the aqueous-ethanolic extract with doxorubicin, a significant reversal in the doxorubicin’s IC50 value by 2.77 folds (p < 0.001, CI = 0.56) was noted as compared to the cytotoxicity test where the extract was absent. The mode of action for the reversal was determined to be synergistic in nature indicating the role of the aqueous-ethanolic extract.

Highlights

The liver is a vital organ that regulates both metabolic and detoxification processes.Disorders pertaining to the liver lead to 2 million deaths annually on a global scale [1].The liver-related mortalities account for the top 15 leading causes of deaths in the United States
The positive mode electron-spray ionization (ESI) analysis of the aq.-ethanolic extract of Suaeda vermiculata led to the identification of nine constituents (Table 1)
Of these nine identified compounds, three flavonoids were identified in the plant extract: One flavonol aglycone, and two flavonol glycosides (quercetin-3-O-rutinoside or rutin, and kaempferol-O-(acetyl)-hexoside-pentoside)

Summary

Introduction

The liver is a vital organ that regulates both metabolic and detoxification processes.Disorders pertaining to the liver lead to 2 million deaths annually on a global scale [1].The liver-related mortalities account for the top 15 leading causes of deaths in the United States. Disorders pertaining to the liver lead to 2 million deaths annually on a global scale [1]. Previous reports on the use of plant-based medications, and investigations of traditionally used herbs, have come back into focus for medicinal purposes, and further drug discovery and development purposes to offer alternative medications to the widely prescribed synthetic-origin drugs for various types of liver disorders. This attention has provided an impetus to newer strategies in drug development for hepatoprotection purposes [7]. The majority of the ameliorating claims regarding the hepatoprotective plants, and herbal formulations, remain unproven, vague, and scientifically unsubstantiated, efforts are still continuously being pushed into the area, and newer plants from varying environments and climatic-condition origins, together with improved testing protocols, are ceaselessly being adopted constantly into the realm of hepatoprotection strategies at global scales [8,9,10,11]

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Conclusion