Lophirones B and C halt acetaminophen hepatotoxicity by upregulating redox transcription factor Nrf-2 through Akt, PI3K, and PKC pathways.

We investigated the mechanism of lophirones B- and C-mediated protection against acetaminophen hepatotoxicity. Mice were pretreated with 20 mg/kg body weight lophirones B and C for 7 days and challenged with acetaminophen on day 7. Acetaminophen raised nuclear factor-κB (NF-κB) in the liver of mice but lowered protein kinase B (Akt). Although, acetaminophen produced no significant alteration on nuclear erythroid related factor-2 (Nrf-2), phosphoinositide 3-kinase (PI3K) and protein kinase C (PKC), lophirones B and C raised the level of these proteins and Akt. The acetaminophen-mediated increase in NF-κB was significantly reversed by lophirones B and C. Lophirones B and C prevented acetaminophen-mediated alterations in serum biomarkers of hepatic injury. Similarly, lophirones B and C lowered the biomarkers of oxidative stress in the liver of acetaminophen-treated mice. It can be inferred from this study that lophirones B and C prevent acetaminophen-induced liver injury by enhancing Nrf-2 through Akt, PI3K, and PKC pathways.