African natural products with potential antioxidants and hepatoprotectives properties: a review

Abstract

Free radicals are highly reactive molecules generated during oxidation reactions which in turn initiate chain reactions resulting to cellular damage. There is substantial evidence implicating free radicals especially reactive oxygen species (ROS) in the etiology of more than one hundred degenerative disorders in humans including, arthritis, atherosclerosis, ischemia and reperfusion injury of many tissues, gastritis, diabetics, central nervous system injury, acquired immunodeficiency syndrome (AIDS) and cancer. Scientific evidence postulates that bioactive compounds especially from natural products are capable of providing protection against free radicals. Consequently, few decades have witnessed a surfeit of research geared towards validating the antioxidant and hepatoprotective potential of the natural products. In this review, African natural products whose antioxidants activities were scientifically validated either in their crude extracts and/or derived products have been discussed. A total 1076 plants species representing 287 family, 132 isolated compounds and 7 insect/mollusk secreation were found. The plant species from the following families; Fababceae, Asteraceae, Lamiaceae, Moraceae, Euphorbiaceae, Combretaceae and Malvaceae have received more scientific attention than others. Analysis of the reports revealed that Combretum apiculatum, Telfaria occidentalis, Acalypha racemosa, Garcinia lucida were the most active plant extracts from African flora. The most active ROS-detoxifying phytochemicals were moracin T, U, S and R (84–87), oleanolic acid (54), 5,7,4′–trihydroxy–3,8,3′,5′–tetramethoxyflavone (89), 5,7,3′–trihydroxy-3,8,4′,5′–trimethoxyflavone (88), luteolin (3′,4′,5,7–tetrahydroxy flavone) (117) and genistein (4′,5,7–trihydroxyisoflavone) (116). The significant antioxidant potential demonstrated by some crude extracts and their constituent compounds render them good candidates for the development of new drugs. Although, the study of the mechanisms of actions as well as clinical validation of some of these isolated compounds is lacking. It is hoped that pertinent scientist and stakeholders will look further into some of these compounds for detailed authentification and subsequent commercialization.

Introduction

Oxidation is a chemical reaction that transfers electrons or hydrogen from a substance to an oxidizing agent. Free radicals are generated during this oxidation reaction especially during oxidative respiration when there is a mitochondria leakage of activated oxygen [1], which in turn initiate a chain of reactions that results in cellular damage. Antioxidants terminate this chain of reactions by removing free radical intermediates, thus inhibiting further oxidation reactions [2]. They include reducing agents such as β-carotene, vitamin C, E and ascorbic acid, as well as enzymes like superoxide dismutase (SOD), catalase (CAT), glutathione and peroxidases [3], and therefore exert their protective role by being oxidized themselves. Furthermore, many antioxidants compounds have been characterized form plants including flavonoids. Flavonoids are phenolic compounds with importants roles in scavenging free radicals and thus play vital roles in preventing oxidative stress associated disorders [4]. Among the common ROS are superoxide (O2^·−), hydroxyl (OH), and peroxyl (OOH, ROO) radicals [5]. Enzymes capable of producing superoxide are xanthine oxidase, reduced nicotinamide adenine dinucleotide phosphate oxidases and cytochrome P₄₅₀ [1]. The imbalance between the production of these free radicals and the detoxifying capacity of the antioxidants results in oxidative stress which is among the major implicative factors in etiology of certain degenerative and chronic diseases including diabetes, atherosclerosis, parkinson’s disease [6], renal disorders [7], cardiovascular, inflammatory, cancer, autoimmune, neurodegenerative diseases [8], and several other human ailments [9].

The liver is the major regulatory organ responsible for the metabolism, storage, detoxification, secretions and excretions of various exogenous and endogenous molecules including xenobiotics [10]. It plays a vital role in maintaining cellular homeostasis and protects the body against deleterious effect of chemicals, drugs, toxin, organism and parasite [5]. Therefore, the healthy performance of the organ reflects the health status of human [11, 12]. However, during these protective roles this organ is susceptible to a numbers of diseases and disorders [13], from chemical drugs and other agents due to its distinctive metabolic roles and the proximal affiliation with the gastrointestinal tract (GIT) [14]. Hepatic injury may also results from excessive alcohol and paracetamol consumptions, exposure to infectious agents, xenobiotics and over the-counter drugs in western countries [15].

Hepatic diseases are a worldwide predicament often involving free radicals induced oxidative stress which if left untreated may advance from steatosis to chronic hepatitis, fibrosis and hepatocellular carcinoma [16]. The conventional drugs commonly used to combat the diseases and disorders associated with the liver are beset with different undesirable effects on biological systems [17]. As a result considerable attentions has been geared towards finding alternative, less toxic and effective antioxidants and hepatocurative agents from Africa natural product for the prevention, managements and treatment of diseases and disorders associated with the liver [18]. The natural products with medicinal reputation could serve as lead sources of natural antioxidants for development of novel drugs [12].

Africa is blessed with enormous biodiversity of natural product for healing practices [19]. From time immemorial Africa medicinal plants have been used by virtually all cultures to meet their health care needs. Evolutions have made plants to harbor a numbers of antioxidant chemicals (phytochemical or secondary metabolites) as natural means of surviving in hostile environments [20]. Consequently, few decades have witnessed a glut of research geared towards validating the quality, quantity, protective roles as well as therapeutic effectiveness of these antioxidant in African plants against oxidative stress induced diseases and disorders.

However, available reviews on the antioxidant potencies of African natural products; focused only on medicinal plants [21], published decade ago with emphasis only on 38 plants [22], others are limited to Cameroonian medicinal plants, [23], few African vegetables, fruits and mushrooms [24], and hepatoprotective activities of medicinal plants [25]. This review is intended to serve as scientific baseline information for the documented African natural products with antioxidants and hepatoprotectve reputation as well as a starting point for future studies.

Methodology (Search strategy)

To identify natural products from African flora and fauna with antioxidant and hepatoprotective potentials, a review was compiled based on scientific literature from various sources including; Google Scholar, Science Direct, PubMed, Medline, Science domain [19, 22, 26, 27]. The keywords used for identification of relevant data included the following terms; antioxidant, radical scavenging activities, anti-aging principles, reactive oxygen species, free radicals, African medicinal plants, natural product, 2,2-Diphenyl-1–picrylhydrazyl radical scavenging assay (DPPH), reducing properties and lipid peroxidations. All relevant data previously published in English were retrieved. However, data for natural products from sources other than African countries were completely excluded from this review paper. Using the specified procedure for acquisition of necessary data, 641 articles were retrieved, out of which 315, mainly in the form of journal articles, books and reviews; were used for compilation of the current review.

The information obtained from these research articles, captured in the current review paper includes; scientific names, that is the family, genus and specific names, parts of plants or mollusk used, solvent system used for the extraction procedure, the bioassay test carried out, whether in vitro or in vivo, as well as the antioxidant and hepatoprotective potencies of natural products originating from African flora and fauna (Tables 1, 2, 3, 4, 5 and 6). Information was also obtained from authenticated post graduate theses, conference proceedings with literature on antioxidant and hepatoprotective assay results of flora and fauna endemic or naturalized in Africa.

Table 1 Antioxidants activities of West African plants

Table 2 Antioxidants activities of Northern Africa African plants

Table 3 Antioxidants activities of Southern AfricaAfrican plants

Table 4 Antioxidants activities of Central African plants

Table 5 Antioxidants activities of Eastern African plants

Table 6 Isolated Compounds from African medicinal plants with antioxidants potential

Results and discussion

A total 1076 plants species representing 287 family and 7 other natural products were identified. Previous phytochemical studies of ethnomedicinal plants of African origin used as antioxidants and for hepatoprotective properties led to characterization of approximately 132 compounds reviewed in this study. A map of Africa indicating the subregions of the continent as used in this review is presented in Fig. 1. From the reviewed plants with antioxidant and related data; 31.33% originate from Northern Africa, 30.97% from Western Africa, 17.98% from Central Africa, 13.98% from Southern Africa, and 5.72% from Eastern Africa (Fig 2). Tables 1, 2, 3, 4, 5 and 6 gives a summary of the plant species that were tested, the family these plants belong to, the parts of the plants that were used to prepare the test samples, the solvent used for the extraction procedure and their potencies in different units depending on the protocol used. The plants that have been extensively studied with regard to these activities belonged to the following families; Fababceae (6.34%), Asteraceae (6.34%), Lamiaceae (5.13%), Moraceae (4.30%), Euphorbiaceae (2.41%), Combretaceae (2.19%), and Malvaceae (1.81%) (Fig. 3). The structures of the compounds isolated from some of the plants with antioxidant activities are presented in (Fig. 4, Additional file 1). The plant parts that were tested for activities included the leaves, stems and stem bark, roots and root bark, pods, flowers and other aerial parts.

Fig. 1

Map of Africa showing the different subregions

Fig. 2

Regional distribution of of investigated African plants with antioxidant potentials

Fig. 3

Percentage occurrence of the most investigated African plants families for antioxidants activities

Fig. 4

Structure of chemical compounds isolated from African plants with potential antioxidants and hepatoprotectives properties (Additional file 1)

A number of procedures have been developed for assessment of in vitro antioxidant potencies of natural products. These protocols are based on two major chemical reactions including; hydrogen atom and electron transfer reactions. To determine the antioxidant potencies of the extracts and compounds using the hydrogen atom transfer mechanisms, one of the following parameters are measured; oxygen radical absorbance capacity (ORAC), total radical antioxidant power (TRAP) and beta carotene bleaching potential. The second category involves electron transfer reactions that measures the following parameters; ferric reducing antioxidant power (FRAP), diphenyl-2–picryl-hydrazyl radical scavenging assay (DPPH), trolox equivalent antioxidant capacity (TEAC), hydroxyl radical scavenging assay, superoxide anion radical scavenging assay, nitric oxide radical scavenging assay and total phenol assay [28]. Despite the recent popularity in antioxidant research, lack of standardized assays to compare research results from different research groups has been a major challenge [29].

The antioxidant potencies of natural products reviewed in this study were categorized based on the degree of inhibitions of free radicals when tested using one or more of the procedures discussed above. In order to increase the reliability of the antioxidant results more than one protocols were used. However, in accordance with the criteria for evaluation of in vitro antioxidant activities of natural products [23, 30, 31], in this report we propose the following cutoff points;

• (1) Extracts and compounds are considered to have high or significant capacity (IC₅₀ < 10 μg/mL for extract and IC₅₀ < 1 μg/mL for compounds), promising activity (IC₅₀ = 10–50 μg/mL for extract and IC₅₀ = 5–10 μg/mL for compounds), moderate activity (IC₅₀ = 50–100 μg/mL for extract and IC₅₀ = 5–10 μg/mL for compounds), while sample with IC₅₀ > 100 μg/mL for extract and > 10 μg/mL for compounds were considered to have low antioxidant capacity.

• (2) Antioxidants activities of plant extracts are considered to be very high when FRAP was > 20 mM/L, high when FRAP was 10–20 mM/L, good when FRAP was 5–10 mM/L, low when FRAP was 1–5 mM/L and very low when FRAP was below 1 mM/L.

• (3) When dealing with radical scavenging activity at a constant concentrat ion. Plant extracts were considered to exhibit low, medium, high and significant activities when their % RSA at 50 mg/mL were observed to be < 25%, 25–50%, 50–80% and > 80%, respectively.

• (4) When dealing with DPPH radical scavenging activities on the basis of degree of color changes extracts are considered to have high or significant capacity when showed strong intensity of yellow coloration, moderate when showed moderate intensity of yellow colouration, and low capacity when showed moderate intensity of yellow colouration

• (5) When dealing with Trolox equivalents (TEAC), antioxidants activities of plants extracts are considered to be very high when activities was < 0.05 and < 0.5 mmol Trolox/g in ABTS and DPPH assay, moderate at 0.05–0.20 and 0.5–1.0 mmol Trolox/g in ABTS and DPPH assay, low at 0.21–0.5 and 1.1–5.0 mmol Trolox/g in ABTS and DPPH assay, while extract with trolox equivalents > 0.5 and > 5 mmol/g in ABTS and DPPH assay respectively are considered inactive.

• (6) When dealing with in vitro hepatoprotective, plant extracts were considered to exhibit significant, medium and low hepatoprotective activities when inhibiting oxidation phenomena of > 80%, 50% and < 50% at concentration ≤ 200 μg/mL respectively

Many antioxidant compounds have been characterized form plants including flavonoids. Flavonoids are phenolic compounds with importants roles in scavenging free radicals and thus play vital roles in preventing oxidative stress associated disorders [4]. The antioxidant effects of flavonoids in biological systems are accredited to its capacity to transport electrons to free radicals, chelate metals, activate antioxidant enzymes, and reduce radicals of alpha-tocopherol or to inhibit oxidases while phenolic compounds exert it antioxidant activities by inactivating free radicals or preventing decomposition of hydroperoxide into free radicals [32]. In this review the antioxidant potential of flavonoids and other phenolic compounds have been highlighted in Table 7.

Table 7 Total phenol, total flavonoids and folic acid content of some African medicinal plants with Antioxidant potential

Evaluations of biochemical parameters including aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), total proteins, albumins, bilirubins, super oxide dismutase (SOD), catalase, malondialdehyde (MDA), glutathione peroxidase have been widely used in assessing the integrity of the liver [33–37]. Therefore, the hepatoprotective capacities of natural products reviewed in this study were assessed based on the levels of ameliorative effect on hapatotoxicants induced alterations in level of these biochemical parameters (Table 8).

Table 8 Hepatoprotective activity of some African medicinal plants

Antioxidant activities of extracts of plants from Western Africa

A total of 341 plants species representing 77 families from Western Africa plants were documented to have antioxidant activities (Table 1). Plant extracts from twenty five plants showed significant antioxidant capacity (IC₅₀ < 10 μg/mL). Fourty eight extracts revealed promising antioxidant activities with IC₅₀ values ranging from 10 to 50 μg/mL; while 59 extracts showed moderate antioxidant activities with IC₅₀ values ranging from 50 to 100 μg/mL.

Oke and Hamburger [38] and Omale [39] presented the antioxidants activities of some medicinal plant on the basis of degree of color changes in which methanol cortex, folium and radix extract of Cnestis ferruginea, funtumia elastica, Gongronema latifolia, Sphenocentrum jollyanum, Voacanga africana and Landolfia owariensis showed strong intensity of yellow coloration in DPPH radical scavenging assay and were considered to have very high antioxidants activities, while Leea gunensis, Hedranthera barteri, Icacina trichantha, Crinum purpurascenc and Byrsocarpus coccineus revealed moderate intensity of yellow colouration. Determination of antioxidant potential on the basis of FRAP, revealed that 9 plant extracts had minimal FRAP (<1 mM/L), 37 including Althaeae radix, Foeniculi fructus, Cetrariae lichen and Phaseoli pericarpum had low FRAP (1–5 mM/L), 15 had good FRAP (5–10 mM/L) while 8 had high FRAP (10–20 mM/L) with the leaf extract of Mellisa officinalis having significant FRAP of 2.52 mM/L [30]. The extract of the leaves of Mellisa officinalis could be considered as the most suitable candidate for development into antioxidant phytomedicine. The constituent compounds should also be evaluated for their antioxidant potential. Phytochemical investigation of plants from Western Africa exhibiting antioxidant and related activities led to isolation of lophirones B (50) and lophirones C (51) (Table 6 and Fig. 3), from chloroform stem bark of Lophira alata. These two compounds show significant antioxidants activities in DPPH assay (84.4%, and 90.0% respectively at 1 μg/mL) and in vivo antioxidants activity [40]. This study shows that treatments of normal rats with 5, 10, and 20 mg/kg body of lophirones B (50) and lophirones C (51) once daily for 2 days increases the activities of ROS detoxifying enzymes (SOD, CAT, GPx, and GR) in the liver of rats when compared to the control.

Antioxidant activities of extracts of plants from Northern Africa

A total of 345 plants species representing 72 families from Northern Africa plants were documented to have antioxidant activities (Table 2). The antioxidant activities of most plant extracts originating from Northern Africa were determined using the free radical scavenging assays carried out at constant concentration of 50 mg/mL, in order to evaluate the % radical scavenging activities (RSA). Using this criteria, plant extracts were reported to exhibit low, medium, high and significant activities when their % RSA were observed to be < 25%, 25–50%, 50–80% and > 80%, respectively. Based on this criteria 39 plant extracts including; Punica granatum, Bombax malabaricum, Schefflera actinophylla, Phalangium variegate, Eucalyptus rostrata, Didonia viscose, Myrtus Communis, Tecoma capensis, Vitex trifolia, Gazania splendens, Lagerstroemia indica, Acalypha marginata, Laurus nobilis, Pelargonium oderatissimum, Khaya senegalensis and Spathodea tilotica had extremely high antioxidant power (>80% inhibition). At 5 mg/mL plant extracts of the following plants; Chrysanthemum frutesence, Aspidistra lurida, Thuja orientalis and Ruscus hyphoglossum exhibited very low antioxidant properties of < 1% RSA. In separate studies the antioxidant activities were determined at relatively higher concentration (100 mg/mL), where Capsicum annuum, Camellia sinensis, Atriplex sp., and Asphodelus microcarpus showed high % RSA [41].

Geographical locations usually influence the accumulation of secondary metabolites in most plants. Variations of these substances may be observed on different parts of the plants used in the study. Solvent systems used for extraction process may also substantially affect the composition of the extracts and hence their bioactivities [4].

The percentage (%) RSA using DPPH of the methanol and chloroform extracts of 124 Egyptian plants was evaluated at 50 mg/mL. The chloroform extracts of these plants were less active demonstrating % inhibition ranging from 0.5 to 49%; while the methanol extracts elaborating more polar compounds showed % inhibition ranging from 3 to 96 % [42].

The variations in scavenging activities of the methanol and chloroform extracts are most probably attributed to the differences in polarities of the phytochemicals [43], and also the classes of compounds extracted by the two solvents. Phytochemical investigation of some plants from Northern Africa exhibiting antioxidant and related activities led to isolation of approximately 56 compounds (Table 6 and Fig. 3). The most potent compounds included; nifedipine (47), trilinolein (42), usnic acid monoacetate (41), 5–bromosalicylaldehyde (39), naphtho [2,1–b]furan-2(1 h)- one,decahydro-3α,6,6,9α–tetramethy (38) and 2,3 dihydroxypropyl elaidate (47) (obtained from the leaf extract of Solanum nigrum) with % RSA of 78.4%, 68.5%, 74%,72.5%, 74% and 76% at 100 μg/mL respectively [44], and catechin (120) obtained from the ethyl acetate leaf extract of Hydnora abyssinica with % RSA of 68.5% at 1 mM [45]. The presence of these important compounds and the significant antioxidants power they demonstrated is an indication that these compounds, if properly screened could yield drugs of pharmaceutical significant.

Antioxidant activities of extracts of plants from Southern Africa

A total of 178 extracts from 145 plants belonging to 43 families were identified from Southern Africa (Table 3). However, the ethanol extract of the bark of Sclerocarya birrea and the leaf extract of Harpephyllum caffrum, Aspalathus lineari and Combretum apiculatum demonstrated the most significant DPPH scavenging activities with IC₅₀ values of 2.06 ± 0.03, 2.6 ± 0.21, 3.5 ± 0.5 and 1.6 ± 0.02 μg/mL, respectively while leaf extract of Galenia africana revealed weak antioxidants activity with an IC₅₀ value of 90.92 ± 1.2 μg/mL [46]. The antioxidant capacity of plant extracts were found to vary with the antioxidant assays used, for instance, Katerere et al. [47] reported Trolox equivalents (TEAC) per 100 g of plant material of Vigna unguiculata, Lippia javanica, Tagetes minuta, Bidens pilosa, Telfairia occidentalis and Corchorus olitarius which ranged from 0.76 to 5.77 mmol Trolox/100 g in ABTS assay and 16.29–1711.22 mmol Trolox/100 g for the DPPH assay. Similarly, Thozama [48] reported the percentage (%) inhibition of Chenopodium album, Solanum nigrum, Urtica lobulata and Amaranthus dubius ranging from 35 to 50% in DPPH assay and from 60 to 75% in ABTS assay. The difference in the antioxidant potencies among the assays was expected as each method has a unique mechanism of action under different reaction conditions [49]. For instance, ABTS⁺ is soluble in both aqueous and organic solvents and thus can be used to determine the antioxidant capacities of both lipophilic and hydrophilic substance [49, 50]. Viol [51] studied the antioxidants activity of 27 Zimbabwe medicinal plants extracts. Eight of these extracts exhibited antioxidant activities using DPPH with the leaves and root extracts of Rhus chirindensis and the bark of Khaya anthotheca exhibiting significant RSA of 96.9% and 96.1%, respectively. However, the roots of Dichrostachys cinerea revealed modest activities with RSA of 27.4% [51].

Antioxidant activities of extracts of plants from Central Africa

A total of 198 extracts from 166 plants belonging to 38 families originating from Central Africa, predominantly from Cameroon, have been investigated for their antioxidant potential (Table 4). The extracts that exhibited the highest antioxidant activities included; methanol extracts of the leaves and stem of Acalypha racemosa with IC₅₀ values of 2.11 and 2.28 μg/mL, respectively; of the fruits and bark of Garcinia lucida with IC₅₀ 1.83 and 2.35 μg/mL, respectively and of the roots and bark of Hymenocardia lyrata with IC₅₀ values of 1.96 and 1.74 μg/mL, respectively [52]. Agbor et al. [53] investigated different extracts of 42 medicinal plants for their antioxidant activities. The methanol extract of the leaves of Harungana madagascariensis, bark of Azadirachta indica, leaves of Psidium guqjava and leaf of Alchornea were considered to have the highest activities using three different assay systems for antioxidant analysis. Detailed phytochemical studies of ethnomedicinal plants from Central Africa having antioxidant activities led to isolation of approximately 62 compounds (Table 6, Fig. 3). The most active compound included; moracin T, U, S and R (84–87) isolated from the bark of Morus mesozygia. These compounds revealed significant DPPH scavenging potential exhibiting IC₅₀ values of 4.12, 5.06, 6.08 and 7.17 μg/mL, respectively [54]. Additionally, Donfack et al. [55], studied the in vitro hepatoprotective activity of six (6) compounds from methanol stem bark of Ficus gnaphalocarpa; betulinic acid (53), catechin (65), quercetin (67), quercitrin (68), epicatechin (66) and 3–methoxyquercetin (64). In this study, simultaneous treatment of hepatoma cells with these compounds exhibited antioxidants and hepatoprotective effects as judged by their ability to prevent liver cell death and LDH leakage during CCl₄ intoxication. The hepatoprotection, showed by the aptitude of these molecules to preserve cellular viability and to inhibit the leakage of LDH in extracellular medium was particularly pronounced with compounds (64, 67–68).

Antioxidant activities of extracts of plants from Eastern Africa

A total of 63 extracts from 51 plants belonging to 23 families were identified to exhibit antioxidant activities (Table 5). Tufts et al. [56] evaluated the ethanol extract of 13 medicinal plants for antioxidant activities using the oxygen radical absorbance capacity (ORAC) assay. Out of these extracts Mangifera indica, Psidium guajava and Ocimum americanum showed the highest antioxidant activities of 5940, 3929 and 3190 μMTE/μg respectively. These extracts also exhibited significant anti-inflammatory effect. The significant antioxidant and anti-inflammatory effect of these plants may confer hepatoprotective virtue to the plants. Detailed phytochemical studies of ethnomedicinal plants from Eastern Africa having antioxidant activities led to isolation of approximately 19 compounds (Table 6, Fig. 3). The most potents of these compounds included; rutin (13) with IC₅₀ of 3.53 μg/ml using DPPH free radicals [57], myricitrin- based glycosides including; myricitrin (20) (IC₅₀ = 14.2 μM), myricetin-3–O-arabinopyranoside (21) (IC₅₀ = 15.8 μM), and quercetin-based glycosides including; quercetin-3–O-diglucosylrhamnoside (14) (IC₅₀ = 20.7 μM) and quercetrin (19) (IC₅₀ = 26.8 μM) [58]. The radical scavenging activities of the quercetin-based glycosides appears to be much higher than those of the kaempferol-based glycosides. This can be attributed to the presence ortho-dihydroxyl groups in the B ring of the former, which is not exemplified in the latter. Similarly, myricitrin-based glycosides which contain ortho-trihydroxy groups in the B ring were shown to be more potent scavengers than their corresponding quercetin-based glycosides. Thus, structure-activity considerations for the present series of flavonoids indicate the importance of multiple OH substitutions for antiradical action towards DPPH with ortho-trihydroxyl group in the B ring elevating the radical scavenging efficiency above that of the ortho-dihydroxyl group.

Hepatoprotective activities of extracts of plants from Africa

The liver is a vital organ which regulates many important metabolic functions and is responsible for maintaining homeostasis of the body [59]. The aetiology of liver diseases is diverse and a variety of plants has been reported to show hepatoprotective activity and so may be useful in the treatment of these diseases [25]. The mechanism of hepatic injury invariably involves peroxidation of hepatocyte membrane fatty acids causing destruction of the cells and their intracellular organelles. Oxidative stress plays a pivotal role in the initiation and progression of hepatic damage following insult to a variety of hepatotoxins [60]. These toxicants damage the hepatocyte primarily by producing reactive oxygen species which form covalent bond with the lipid moiety of the hepatic cell membranes. The drugs/chemicals and plants with antioxidant properties have been shown to protect against toxin induced hepatotoxicity through inhibition of the generation of free radicals. A list of plants reported to have significant hepatoprotective activity is shown in Table 8 in alphabetical order of their family, together with their scientific names, origin, plant part used, kind of extract used, type of assay and inducer of liver damage. Most of these planta are discussed in greater details below.

Moringa oleifera

Moringa oleifera Lam. (Moringaceae) locally known as “ben oil or drumstick tree” is a small, graceful, deciduous tree with sparse foliage [61]. The plant grows abundantly in many tropical and subtropical countries. Moringa is an ancient magic plant with a plethora of medicinal and nutritional value. The leaves, flowers, root, gums, fruit, and seed of M. oleifera have been extensively used in traditional medicine for the treatment of liver disease, lipid disorders, arthritis, and other inflammatory disorders [62]. The ethanolic extract of the leaves of M. oleifera was found to exhibit hepatoprotective effect against alcohol induced hepatotoxicity in rats [63]. This research proved that animal pretreatment with ethanolic extract of M. oleifera (300 mg/kg of weight) significantly attenuated hepatotoxin induced biochemical (serum AST, ALT, ALP, and GGT) and histopathological changes in the liver. Additionally, M. oleifera leaves also showed significant anti-inflammatory [64], and antioxidant potencies [63], [65], which may be contributing to its hepatoprotective activity. A number of phytochemicals with antioxidant activities have been characterized from Moringa oleifera including; quercetin (22), rutin (13), kaempferol and caffeoyqumic acids.

Senna alata

Senna alata (L.) Roxb) (Fabaceae) is commonly known as candle bush, with reference to the shape of its inflorescences, or ringworm tree for it traditional use. It is an annual, erect, tropical herb of 0.15 m high [66]. The leaves are well known for their medicinal used for various diseases of the liver [67]. The hepatoprotective effect of the plant has been shown in Wistar albino rat intoxicated with CCl₄. This study reported that methanol extract and fractions (ethanol and butanol) of S. alata leaves administered orally at 400 mg/kg decreased hepatic enzyme levels (serum ALT, AST, ALP,) total and direct bilirubin, liver TBARS induced by CCl₄ damage. Administration of the methanol extract of this plant showed maintenance of the hepatocytes membrane’s structural integrity [68]. The extract also showed strong antioxidant and anti-inflammatory [69], activities which may contribute to its hepatoprotective property.

Cochlospermum tinctorium

Cochlospermum tinctorium (Cochlospermaceae) is a bushy savannah plant, commonly found in fallow farms across northern Nigeria. It is a shrub that grows up to 10 m high [70]. Decoctions of the whole roots of C. tinctorium have been reported to be used as remedy for gonorrhoea, jaundice, gastrointestinal diseases, helminthes, bilharzias infest ations, as well as for the management of epilepsy [71]. The hepatoprotective effect of methanol extracts of C. tinctorium leaf has been studied against CCl₄ induced liver injury [72]. The extract attenuated CCl₄ induced rise in liver enzymes including AST and ALT, bilirubin, MDA level and prevented histopathological alterations in the liver [72]. The hepatoprotective activities of the extract have been linked to both enzymic and non-enzymic antioxidants that could bring about free radical suppressing activity.

Uvaria afzelii

Uvaria afzelii Sc Elliot (Annonaceae) is widely distributed and grown in the South and eastern part of Nigeria, where it is known by various local names such as “gbogbonishe” (Yoruba), “Umimi ofia” (Igbo) and “Osu-umimi” (Ukwani) [73]. Locally it is used in the treatment of cough, vaginal tumour, gonorrhea, jaundice, infections of the liver, kidney and bladder [74, 75]. The hepatoprotective activity of this plant was evaluatedin the experimental acute hepatic damage induced by CCl₄ in rat [76]. In this study, it was reported that the methanolic extracts of the root of Uvaria afzelii, at doses of 125 mg/kg, 250 mg/kg and 500 mg/kg, significantly reduced the serum hepatic enzymes, total and un-conjugated bilirubin. Phytochemical studies of this plant has shown the presence of syncarpic acid, dimethoxym atteucinol, emorydone, 2–hydroxydemethoxym at-teucinol, uvafzelic acid, syncarpurea, afzeliindanone, flavonoids, triterpenoids and phenols [76–78]. Some of these compounds have also been credited for their antiparasitic and antioxidant activities [79].

Sphenocntrum jollyanum

Sphenocntrum jollyanum Pierre (Menispermaceae) is locally known as Aduro kokoo (red medicine) and Okramankote (dog’s penis) in Ghana. It is a small erect sparsely branched rub which grows up to 1.5 m in height. Different part of S. jollyanum has been used extensively for the treatment of various ailments in Western Africa Sub-region. The methanolic extract of S. jollyanum stem bark showed significant hepatoprotective activity against CCl₄ induced liver injury [80]. In addition, this extract possesses significant antioxidant activities with IC₅₀ values of 13.11 and 30.04 μg/mL in superoxide and hydrogen radical scavenging activity, respectively [80] and anti-inflammatory [81], activities which may be contributing to its hepatoprotective effects.

Khaya grandifoliola

Khaya grandifoliola (Meliaceae) is commonly used in traditional medicine by the Bamun (a tribe of Western Cameroon) for curing liver related diseases [82]. The hepatoprotective effect of K. grandifoliola has been studied against PCM [83], and CCl₄ induced hepatotoxicity [84] in rats. The methanol; methylchloride extract of the stem bark of this plant at 25 and 100 mg/kg dose dependently attenuated hepatotoxin induced alterations in biochemical parameters (serum ALP, AST, ALT and TP and liver TBARS, SOD, GSH and GR) and prevented toxin induced alteration in liver histopathology. The extract also showed antioxidant and anti-inflammatory activities [84] which may be contributing to its hepatoprotective activity.

Spathodea campanulata

Spathodea campanulata, (Bignoniaceae), it’s a widely used traditional African medicinal plant for skin diseases and stomach aches [85]. The extract of the stem bark of Spathodea campanulata produced significant hepatoprotection [86]. In this study it was reported that the methanolic extracts of the stem bark of S. campanulata, at doses of 100, 300, and 625 mg/kg significantly attenuated CCl₄ induced rise in biochemical (serum AST, ALT and GGT) and histopathological changes in the liver [86]. Phytochemical studies on S. campanulata showed the presence of flavonoids, tannins, spathoside, n-alkanes, linear aliphatic alcohols, beta-sitosterol-3–O-beta-D-glucopyranoside, oleanolic acid, pomolic acid, p-hydroxybenzoic acid, phenylethanol esters, reducing sugars. The in vitro testing which gave positive results for reducing power and total phenolic content [86–88], also support the activity of the plant extract with reference to its hepatoprotection.

Vernonia ambigua

Vernonia ambigua (Asteraceae) is an annual shrub growing up to 6 m high. It is widely distributed in areas like Angola, Sudan, Tanzania, Uganda and tropical Western Africa. In Nigeria it is used for gastrointestinal disorders, as a general tonic and appetite stimulant, for skin diseases and as a medication for fever, dysentery, malaria, diabetics and constipation [89]. The hepatoprotective activity of leaf extract of V. ambigua has been investigated using CCl₄ induced hepatotoxicity in albino rats. The extract significantly attenuated CCl₄ induced biochemical (ALT, AST and ALP, TB, CHOL, TGA, TP and ALB [90]. Plants of the genus Vernonia are known to produce characteristic compounds such as sesquiterpene lactones, with several reported biological activities, such as fungistatic [91], and cytotoxic activities [92]. The hepatoprotective properties of plants from genus Vernonia may be attributed to presence of mainly; flavonoids, steroids and polysaccharides [93], that has been characterized previously from this genus.

Ocimum americanum

Ocimum americanum (Lamiaceae) commonly known as “African basil” It is a wild herb with a distinct mint flavor, hairy leaves and scented flowers that is native to tropical Africa. The aqueous extract of O. americanum (200 and 400 mg/kg) significantly attenuated PCM induced biochemical (serum ALP, AST, ALT and TBIL level) and histopathological alterations in the liver [94]. The hepatoprotective activity of Ocimum americanum may be attributed to its antioxidant activities [95].

Tulbaghia violacea

Tulbaghia violacea (Alliaceae) is a fast-growing, bulbous plant that reaches a height of 0.5 m. In the Eastern Cape of South Africa rhizomes of Tulbaghia violacea has been used for the treatment of jaundice, gall bladder stones, liver diseases and heart disease [96]. The rhizomes extract of T. violacea dose dependently attenuated atherosclerogenic induced alteration in markers of endothelial dysfunction, lipid profile, liver enzymes and histological changes [97]. The antioxidant and cytotoxicity activities of T. violacea as well as its phytochemical components such flavonoids and saponins [98] may be responsible for its hepatoprotective properties.

Irvingia gabonensis

Irvingia gabonensis (Irvingiaceae) locally known as “bush mango or African mango” since the trees bear fruits that look like small mango (Matos et al., 2010). In Senegal, the decoction of the stem bark is used in the treatment of gonorrhoea, hepatic and gastrointestinal disorders [99]. The thanol extract of the leaves of this plant has been investigated for its hepatoprotective activity in sodium arsenite (SA) induced hepatotoxicity and clastogenicity in male Wistar rats [100]. The extract at 250 or 500 mg/kg dose dependently attenuated sodium arsenite induced rise in liver enzymes including AST, ALT and and gamma glutamyltransferase (γGT) and prevented histopathological alterations in the liver [100]. Phytochemical studies on the ethanol extract of Irvingia gabonensis showed the presence of of tannins, saponins, alkaloids, terpenoids, flavonoids and phenols [100]. Tannins have been reported to have anti-inflammatory and antiulcer property in rodents and they also exhibit strong antioxidant properties [101].

Echinops galalensis

The methanol extract of the flowering aerial parts of Echinops galalensis (Asteraceae), its fractions and the isolated compounds (25–33) have been reported for their hepatoprotective effects agaisnt CCl₄ induced cell damage in an in vitro assay on human hepatoma cell line (Huh7). The extract and isolated compounds (25–33) at 100 μg/mL prior to CCl₄ challenge protected against cell injury by decreasing the level of AST, ALT, MDA and increasing the activities of SOD [102]. The protective effects of E. galalensis methanolic extract, its fractions as well as the isolated compounds is at least partly due to their antioxidant activities as evidenced by the reduction in MDA level and the increase in SOD activity.

Lawsonia inermis

Lawsonia inermis (lythraceae) is a shrub or small tree cultivated in many regions as an ornamental and commercial dye crop [103]. It is mostly found in the tropic, sub-tropic, and semi-arid zones of Africa (tropical Savannah and tropical arid zones), South Asia and North Australia [104]. As a medicinal plant, the leaves, seed and bark of L. inermis have been used in folk remedy as astringent, hypotensive, sedative, and against a headache, jaundice, spleen enlargement, leprosy and other liver disease [105]. Its hepatoprotective activity was shown in a toxicity model by CCI₄ in rats. These research proved that animal pretreatment with a methanolic extract of Lawsonia inermis (100 and 200 mg/kg of weight) attenuated the increase in AST serum activity, alanine aminotransferase (ALT), alkaline phosphatase (ALP), total bilirubin (TB), and histological changes observed in the damage induced by CCl₄ [106, 107]. Previous reports have shown that L. inermis is rich in phenolic compounds such as phenolic acids, flavonoids, tannins, lignin, and others that possess antioxidant, anticarcinogenic, and antimutagenic effects as well as antiproliferative potentials [108], which may be responsible for its hepatoprotective activities.

Ficus chlamydocarpa

Ficus chlamydocarpa (Moraceae) is traditionally used in Cameroon for the management of different diseases including; filarial, diarrheal infections and tuberculosis [109]. Another ethnopharmacological survey has revealed that a decoction of the stem bark is used in West Cameroon folk medicine for the treatments of abdominal problems, arthritis, inflammatory conditions and jaundice, which are commonly considered symptomatic of liver-related diseases.

Its hepatoprotective effect was evaluated through the induction of acute hepatic damage in rats using CCl₄ [99]. In this, study the pre-treatment with 50–200 mg/kg of methanolic extract of F. chlamydocarpa stem bark prevented serum increase of hepatic enzyme markers and lactate dehydrogenase (LDH), enhanced hepatic reduced glutathione (GSH) level and decreased of hepatic malondialdehyde (MDA) during CCl₄ intoxication. Previous phytochemical studies on stem bark of F. chlamydocarpa revealed the presence of the following flavonoids; alpinumisoflavone (115), genistein (4′, 5, 7– trihydroxyisoflavone 116) and luteolin (3′, 4′, 5, 7– tetrahydroxy flavones 117) with significant DPPH radical scavenging activities with IC₅₀ (μg/mL of 6, 5.7, 5.0 respecively [99].

Allanblackia gabonensis

Allanblackia gabonensis (Guttiferae) is commonly grown in tropical Africa including; Cameroon, Democratic Republic of Congo, etc. between around 500 and 1750 m above sea level [110]. The plant is used in traditional medicine to treat some inflammatory diseases. The aqueous suspension of the stem bark of A. gabonensis showed significant hepatho-nephroprotective activity against acetaminophen-induced liver and kidney disorders in rats. In this, study the pre-treatment with 100 and 200 mg/kg significantly reduced the serum level of MDA, increase in enzymatic antioxidant activities (SOD and CAT) and non enzymatic antioxidant (GSH) levels [111]. The stem bark of this plant has been known to elaborate the following compounds xanthones, benzophenone, flavonoide, and phytosterol [112]. In addition, A. gabonensis possess significant analgesic and anti-inflammatory activities [113] which may be contributing to its hepatoprotective activities.

Ficus exasperata

Ficus exasperata vahl (Moraceae) is a terrestrial plant that grows 20 m high and inhabits the evergreen and secondary rainforest of West Africa. The plant is commonly known as sand paper tree, it is also known locally as “anwerinwa” [114]. The ethanol extracts of the leaves of F. exasperata showed significant hepatoprotective activitie in acetaminophen-induced hepatotoxic rats [115]. The extract at 125–500 mg/kg significantly ameliorated toxin induced alterations in the liver ALT, AST, ALP and bilirubin levels. The histological evaluation showed a partial prevention of inflammation, necrosis and vacuolization induced by CCl₄ [115].

Erythrina senegalensis

Erythrina senegalensis DC (Fabaceae), locally known by the Bamun people in Cameroon as ‘Megham njû’ is a thorny shrub or small tree, with a corky stem bark and bright red flowers, found in Sudanese savannah regions. Hepatoprotective effect of the ethanolic extract of Erythrina senegalensis stem bark was studied in vivo against CCl₄₋induced induced liver damage as well as in vitro against rat liver slices intoxicated CCl₄. E. senegalensis extract at 100 mg/kg significantly attenuated hepatotoxin induced biochemical serum ALT, AST and lipid peroxidation in liver homogenate. Polyphenols including flavonoids have been characterized from this plants which could be implicated for its hepatoprotective potential [116].

Njayou et al. [117], evaluated the hepatoprotective effect of fifty four Cameroonian plants extracts against Fe (II)-Ascorbate induced microsomal lipid peroxidationin rat liver. Only 15 plants extract inhibiting oxidation phenomena with percentage inhibition of > 50 at 200 μg/mL were considered as possessing a high lipid oxidation inhibitory potential. In this respect, Mangifera indica, Enantia chlorantha, Voacanga africana, Aspilia africana, Senna alata, Piliostigma thonningii, Piliostigma thonningii, Kalonchoe crenata, Alchornea laxiflora, Crotalaria lachnophora, Erythrina senegalensis, Khaya grandifoliola, Entada africana, Melinis minutiflora and Curcuma longa were found to be active. Among these active plant species, some of them, namely E. chlorantha [118], E. africana [119] and C. longa [120], have been reported to be active against experimentally induced hepatitis. M. indica on its part has been shown to be very effective against lipid and protein oxidation in vitro and injury associated to hepatic ischemia reperfusion [121, 122]. The inhibitory effect against the free radical-mediated degradation of microsomal lipid peroxidation by plant extracts mentioned above may also be attributed to flavonoids and polyphenols as many of these phytoconstituents are known to be antioxidants [123]. The presence of flavonoids and polyphenols has been reported in all the above cited plant extracts [124, 125].

Aja et al., [2], documented the antioxidant activities of the ethanol leaf extracts of C. citratus and H. spicigera against Plasmodium berghei induced oxidative stress by significantly (P < 0.05) increasing the superoxide dismutase, reduced glutathione, catalase and peroxidase activities and decreasing the lipid peroxidation when compared with the controls. This study indicates the effectiveness of the use of Cymbopogon citratus and Hyptis spicigera in the management of oxidative stress caused by malaria [2].

Mulata et al. [126], evaluated the effect of hydroethanolic seed extract of Calpurnia aurea against highly active antiretroviral therapy (HAART) induced free radical reactions in the liver and liver cell damage in rats. The authors reported that the extract (300 mg/kg) reduced the HAART induced liver toxicity by decreasing the free radical reactions, ALP, ALT, AST release and increasing antioxidant profiles in treated rats.

A polyherbal formulation comprising of Gongronema latifolia, Ocimum gratissimum and Vernonia amygdalina demonstrated significant hepatoprotective activities by attenuating the increase in serum hepatic enzyme levels after CCl₄ treatment compared to the toxin control group and increasing the levels of serum CAT, GPx, GSH, GST, SOD, total protein and significantly (p < 0.05) decreasing lipid peroxidation compared to the toxin control group [127].

“Ata-Ofa” a polyherbal formulation consisting of twenty one (21) plant products, including, Ginger officinalle, Tamarindus indica, Khaya senegalensis, Moringa oleifera, Nauclea latifolia, Camellia sinensis, Anacardium occidentale, Aframomum melegueta, Phyllantus amarus, Morinda lucida and Mangifera indica was reported (at 5 mg/kg) for in vivo antioxidant, hepatoprotective and curative effects by its ability to ameliorate CCl₄ induced alterations in biochemical parameters and antioxidants enzymes in intoxicated rat [128].

Antioxidants and hepatoprotective activities of insect/mollusk and their secreations

Omalu et al. [129], evaluated the free radical scavenging activity of Nigeria Leech (Aliolimnatis michaelseni) saliva extract. Their results revealed that the extract excert significant DPPH free radical scavenging activity with IC₅₀ value of 8.169 μg/mL initially and 8.67 μg/mL after starvation for 1 month. Omalu et al., [130], also documented the antioxidants potency of maggots of the blowfly (Lucilia robineau) excretion/saliva extract with DPPH free radical scavenging activity of (IC₅₀ of 152.66 μg/mL) compared with 108.99 μg/mL of L-ascorbic.

Giant African Snail (Achachatina maginata) haemolymph has been reported for in vitro antioxidant activity with an IC₅₀ value of 579.66 ± 2.69 μg/mL in DPPH radical scavenging assay and 310.75 ± 3.12 μg/mL in lipid peroxidation inhibitory assay. The haemolymph also excert ameliorative effects on CCL₄₋induced elevations of the levels of AST, ALT, ALP, TBARS and it reversal effect on reduced concentration of catalase induced by CCL₄ intoxication. The total phenolics and flavonoids contents were reported to be 9.30 ± 0.11 mg/g GAE and 15.20 ± 0.59 mg/g catechin equivalent respectively [5].

Shittu et al. [131], reported the ameliorative effects of the methanol extracts of Musca domestica (400 mg/kg) against T. brucei induced alteration in antioxidants enzymes (SOD and CAT). Antioxidant screening of the extract against DPPH was positive, with IC₅₀ and antioxidant activities index (AAI) of 174.38 mg/mL and 0.29 respectively. Since oxidative stress has been implicated in the etiology of African trypanosomiasis, these two findings suggest that the methanol extract of Musca domestica probably excert it anti-trypanosoma effect by free radical scavenging and thus could serve as a candidate for the development of new drugs for the treatment of trypanosomiasis. The methanol extracts of Nigeria bee propolis (600 mg/kg) has been reported for hepatocurative effect by ameliorating CCL₄₋induced alterations in the serum and liver AST, ALT and ALP activities when administered orally to rats for 10 days [132].

Tanzania honey bee has been reported for DPPH radical scacvenging activity with IC₅₀ 4.19, 12.93 and 18.03 mg/mL in stingless bee honeys, raw bees honey and processed bees honey respectively. Similarly, iron chelating activities were reported with IC₅₀ value of 0.04, 0.057 and 0.158 mg/mL for stingless bee’s honey, raw bee’s honey and processed bee’s honey respectively [133]. Previous phytochemical investigation of the Nigerian sweet and bitter honey revealed total flavonoids contents of 20.81 μg/mL and 18.92 μg/mL respectively [134].

Nyanzi et al., [135], reported the antioxidant activities of methanol extract from freeze-dried cells of probiotic Lactobacillus strains. At the extract concentration of 20 mg/mL the authors reported that Lb. acidophilus, Lb. rhamnosus and Lb. casei strains had DPPH scavenging activities of 77.9–86.1%, 45.7–86.4% and 36.9–45.8% respectively. This finding is an indication that Probiotic extracts can potentially be used as bio-preservatives and in reduction of oxidative stress.

Conclusion and future prospects

Meta-analysis of available scientific literature on antioxidants and hepatoprotective activity of African natural products to a great extent validate folkloric claims about the usefulness of these botanicals to treat liver diseases and other oxidative stress induced disorder. This review has documented the list of African natural products with potential antioxidants and hepatoprotectives effect. Many of these natural products displayed good antioxidants and hepatoprotective activities. This explains the effort of Africa research institutes in drug discovery from natural products. However, the variations in method of analsis, presentations of results, doses, durat ion as well as the geographical difference of the plants reviewed in this study has made it difficult to accurately point out plant/compounds with the best reported antioxidants and hepatoprotective activities. But our close analysis of the reports seem to suggest that Combretum apiculatum, Telfaria occidentalis, Acalypha racemosa, Garcinia lucida, Xeoderris sthulmannii, Clausena anisata, Harpephyllum caffrum, Ceratotheca sesamoides, Camellia sinensis, Cyathea dregei, Harpephyllum caffrum, Aspalathus linearis were the most active ROS-detoxifying plant extracts from African flora. The best ROS-detoxifying phytochemicals were moracin T, U, S and R (84–87), oleanolic acid (54), 5,7,4′–trihydroxy–3,8,3′,5′–tetramethoxyflavone (89), 5,7,3′–trihydroxy–3,8,4′,5′-trimethoxyflavone (88), luteolin (3′,4′,5,7–tetrahydroxy flavone) (117) and genistein (4′,5,7– trihydroxyisoflavone) (116). It is hoped that pertinent scientist and stakeholders will look further into some of these plants and compounds for detailed authentification and subsequent commercialization. Although, most of studies reviewed are preliminary in nature, detailed isolation, characterization, mechanisms of actions of these of isolated compounds, safety studies, quality control as well as clinical trials on some of these herbs and their isolated compounds is far from satisfactory.