Key words: Hepatotoxicity, oxidative stress, antioxidants, Pterocarpus santalinoides leaf extract, carbon tetrachloride.
The liver is a vital organ for metabolism, excretion, clearance and transformation of chemicals in the body
(Singh et al., 2011). It is responsible for the detoxification of drugs and xenobiotics; thus, it is constantly and
variedly exposed to xenobiotics which may induce liver damage (Saukkonen et al., 2006). Most absorbed toxins and toxicants will first pass through liver, and the possible response elicited may range from inflammation to degeneration and/or neoplasia of the hepatocytes (Schiff and Schiff, 1987). Hepatotoxicity is a major health problem, and the manifestations vary from asymptomatic elevation of liver enzymes to fulminant liver failure (Saukkonen et al., 2006). Toxic liver damage is commonly oxidative stress mediated, and constitutes a large proportion of liver disorders/diseases; its occurrence has been steadily increasing over the years (Suk and Kim, 2012, Rehm et al., 2013; Nwokediuko et al., 2013).
Carbon tetrachloride (CCl4) is a commonly used model chemical for the experimental induction of hepatotoxicity (Kim et al., 2010). It is metabolized to trichloromethyl (CCl3) free radical which induces hepatotoxicity by causing peroxidative degradation in the adipose tissue, resulting in fatty infiltration of the hepatocytes (Boll et al., 2001). Following administration, CCl4 is activated by cytochrome CYP2E1 and CYP2B1 to form CCl3 radical which binds to cellular molecules such as nucleic acids, proteins and lipids, thereby impairing crucial cellular processes like lipid metabolism, with the potential outcome of fatty degeneration (Boll et al., 2001). The CCl3 radical reacts with oxygen to form highly reactive species, the trichloromethylperoxy (CCl3OO) radical, which initiates the chain reaction of lipid peroxidation culminating in destruction of polyunsaturated fatty acids (Boll et al., 2001). This causes alteration in permeability of the mitochondria, endoplasmic reticulum, and plasma membranes, resulting in the loss of cellular calcium, disruption of calcium homeostasis and damage/death of hepatocytes (Weber et al., 2003).
Oxidative stress is a state in which oxidation and oxidants exceed the antioxidant systems in the body leading to imbalance between the generation of reactive oxygen species (ROS) and the level of antioxidants in the biological system (Yoshikawa and Naito, 2002). It occurs when free radicals which are not neutralized by antioxidants go on to create more volatile free radicals and damage cell membranes, vessels, proteins, fats and DNA. Biological free radicals are highly unstable reactive molecules that have electrons available to react with various organ substrates such as DNA, proteins and lipids. Oxidative stress is known to be involved in the pathogenesis of a variety of diseases including atherosclerosis, hypertension, diabetes mellitus, ischemic diseases, liver diseases and malignancies (Yoshikawa and Naito, 2002), or may exacerbate their symptoms (Halliwell and Gutteridge, 1989; Valko et al., 2007).
Antioxidants are compounds that inhibit the oxidation of other compounds and prevent chemical damage caused by free radicals (Sies, 1997). Oxidation reactions in living organisms produce free radicals which can initiate chain reactions that may cause damage or death to cells.
Antioxidants terminate these chain reactions by removing free radical intermediates and inhibiting other oxidation reactions (Sies, 1997; Valko et al., 2007). Insufficient levels of anti-oxidants or inhibition of the antioxidant enzymes in living organisms cause oxidative stress which may lead to injury and/or death of cells (Davies, 1995; Valko et al., 2007). Many of the natural antioxidants such as tannins, flavonoids and glycosides are very important in the prevention of diseases associated with oxidative stress (Yi-Fang et al., 2002; Aruoma, 2003).
Some plants such as Cussona barteri (leaves), Lannea vilutina (leaves), Sacoglotis gabonensis (stem bark), Trichilia roka (roots), Tinospora cordifolia (whole plant), Piptadeniastrum africanum (stem bark) and Gongronema latifolium (leaf) amongst others, have been reported to be rich sources of natural antioxidants that can protect against oxidative stress and thus play important role in the chemoprevention of diseases that have their etiology and pathophysiology in ROS (Ames et al., 1993; Atawodi, 2005; Karamalakova et al., 2018; Dlamini et al., 2019). There has been an increase in interest in the therapeutic potential of plants as antioxidants that may reduce free radical-induced tissue injury (Schuler, 1990; Karamalakova et al., 2018). A number of plants such as Ipomoea batatas (leaves), Allium cepa (leaves), Cnestus ferruginea (leaves stem and roots), Splenacentrum jollyanum (leaves and roots) and Voacanga africana (leaves) had been investigated in the search for novel antioxidants (Chu, 2000; Mantle et al., 2000; Koleva et al., 2002; Oke and Hamburger, 2002), while a lot more are still under investigation.
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