Abstract
Aim of the study: High dose acetaminophen (APAP) increases the risk of liver injury caused by oxidative stress due to accumulation of reactive species. Although N-acetyl cysteine is the standard antidote used to treat acute APAPinduced liver failure, we proposed that known antioxidant phytochemicals in Leonotis nepetifolia extracts would protect against APAP-induced hepatic injury by modulating the activities of antioxidant enzymes. Materials and methods: Methanol and aqueous extracts of L. nepetifolia were orally administered in doses ranging (250 mg/kg to 1000 mg/kg) as pre- and post-treatment with high dose APAP (550 mg/kg) to Swiss albino mice. Twenty-four hours after the final dose, animals were euthanized and blood and liver collected for liver enzymes (ALT and AST), histological assessment and antioxidant enzyme assays. Results: Methanol and aqueous extracts as pre-treatment and post-treatment protected against hepatic injury. Extracts abrogated the 14-fold and 4-fold APAP-induced increases in ALT and AST respectively, including histopathological damage (p<0.05). Extracts reversed APAP-induced 4-fold and 14-fold increases in GR and SOD activities respectively (p<0.05). Additionally, extracts reversed APAP-induced decline in GPx activity; particularly the aqueous extract as pre-treatment increased GPx activity up to 2.2-fold over saline-treated controls (p<0.05). Conclusions: Extracts, as pre-treatment and post-treatment, prevented APAP-induced hepatic injury by modulating the activities of antioxidant enzymes. Of particular interest, is the reversal of APAP-induced decrease in GPx activity and increase in SOD activity? Extract-induced increase in GPx activity would facilitate the scavenging of hydroperoxide and peroxide reactive species generated by high dose APAP. We propose that antioxidant phytochemicals in L. nepetifolia may be acting as free radical scavengers which results in reduced SOD activity.
Highlights
The liver is the major organ responsible for the metabolism of xenobiotics and it is susceptible to drug-induced injury, including drug overdose and deleterious drug-drug interactions
Of particular interest, is the reversal of APAP-induced decrease in Glutathione Peroxidase (GPx) activity and increase in Superoxide Dismutase (SOD) activity? Extract-induced increase in GPx activity would facilitate the scavenging of hydroperoxide and peroxide reactive species generated by high dose APAP
We propose that antioxidant phytochemicals in L. nepetifolia may be acting as free radical scavengers which results in reduced SOD activity
Summary
The liver is the major organ responsible for the metabolism of xenobiotics and it is susceptible to drug-induced injury, including drug overdose and deleterious drug-drug interactions. Acetaminophen (APAP) is widely used as an over-the-counter analgesic and antipyretic. It is the drug most commonly associated with drug-induced hepatic injury requiring hospitalization, making it a serious public health concern. Persons at risk for hepatic APAP injury include patients prescribed high daily doses (more than 4 g/day) on a long-term basis [1], as well as those who intentionally or accidentally overdose [2,3,4]. At therapeutic doses APAP is primarily detoxified by Phase 2 enzymes to inactive conjugates with minute amounts being metabolized by CYP2E1 to the short-lived, but highly reactive, NAPQI. At high doses Phase 2 conjugation pathways become saturated and more APAP is converted to NAPQI, depleting glutathione stores and causing accumulation of this highly reactive species. The precise mechanism of APAP-induced hepatotoxicity is not fully understood, it is proposed that NAPQIinduced oxidative stress culminates in cellular necrosis and lipid peroxidation [5]
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