Models of drug-induced liver injury for evaluation of phytotherapeutics and other natural products

Abstract

Extracts from medicinal plants, many of which have been used for centuries, are increasingly tested in models of hepatotoxicity. One of the most popular models to evaluate the hepatoprotective potential of natural products is acetaminophen (APAP)-induced liver injury, although other hepatotoxicity models such as carbon tetrachloride, thioacetamide, ethanol and endotoxin are occasionally used. APAP overdose is a clinically relevant model of drug-induced liver injury. Critical mechanisms and signaling pathways, which trigger necrotic cell death and sterile inflammation, are discussed. Although there is increasing understanding of the pathophysiology of APAP-induced liver injury, the mechanism is complex and prone to misinterpretation, especially when unknown chemicals such as plant extracts are tested. This review discusses the fundamental aspects that need to be considered when using this model, such as selection of the animal species or in vitro system, timing and dose-responses of signaling events, metabolic activation and protein adduct formation, the role of lipid peroxidation and apoptotic versus necrotic cell death, and the impact of the ensuing sterile inflammatory response. The goal is to enable researchers to select the appropriate model and experimental conditions for testing of natural products that will yield clinically relevant results and allow valid interpretations of the pharmacological mechanisms.

Proximate Composition, Amino and Fatty Acid Profiles and Element Compositions of Four Different Moringa Species

“…The large discrepancy in scientific interest is likely based on several important and advantageous properties of M. oleifera; of which the most important and well known is probably the coagulation ability of specific seed proteins (Olsen, 1987;Gassenschmidt et al, 1995;Muyibi & Evison, 1995;Ndabigengesere, Narasiah, & Talbot, 1995;Ndabigengesere & Narasiah, 1998). Other reasons that M. oleifera has been the focus of study are the potential utilization of the seeds as a feed additive (Ben Salem & Makkar, 2009;Hlophe & Moyo, 2014; T. P. Singh, P. Singh, & Kumar, 2015) or insecticide (Benelli, 2015); the importance of the leaves for human nutrition (Subadra, Monica, & Dhabhai, 1997;Babu, 2000;Fahey, 2005;Thurber & Fahey, 2009); including its potential use as a human famine food (Sena et al, 1998) and as animal feed (Richter et al, 2003;Negesse, Makkar, & Becker, 2009;Abbas, 2013) and the medical potential of all plant parts (Anwar et al, 2007;Jaeschke, Williams, McGill, Xie, & Ramachandran, 2013); including the antibiotic activity of pods, flowers and leaves (Brilhante et al, 2015).…”

Hepatoprotective and antioxidant effects of <i>Cymbopogon citratus</i> Stapf (Lemon grass) extract in paracetamolinduced hepatotoxicity in rats

“…The increase in MDA level in liver, which can be induced by PCM intake, suggests enhanced lipid peroxidation and is an indicator of hepatic tissue damage [14,15]. Beside the depletion of glutathione, NAPQI can exert initial cell stress through a wide range of mechanisms including binding to enzymes, lipids, nucleic acids, and other cell structures [16].…”

Adverse Outcome Pathway on Protein Alkylation Leading to Liver Fibrosis

“…Assuming hepatocyte injury being the crucial KE without which fibrosis could not occur via this AOP, then simple investigation of in vitro hepatotoxicity could provide relevant information for potential fibrosis prediction without the need of highly elaborated cell models. The initial AOP case study was based on data of two prototypic fibrogenic chemicals, namely Carbon Tetrachloride (CCl4) (Basu, 2003;Brattin et al, 1985;Calabrese and Mehendale, 1996;Calabrese et al, 1993;Clawson, 1989Dalu and Mehendale, 1996;EPA, 2010;Feng et al, 2011;Jaeschke et al, 2013;Jang et al, 2008;Lee et al, 2004;Li L. et al, 2012;Li X. et al, 2013;Luster et al, 2000;2001;Lv et al, 2012;Masuda, 2006;Morio et al, 2001;Nagano et al, 2007;Natsume et al, 1999;Neubauer et al, 1998;Nissar et al,2013;Park et al, 2004;Recknagel, 1976;Simeonova et al, 2001;Tipoe et al, 2006;Weber et al, 2003;Zhu and Fung, 2000) and Allyl…”