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A previous pharmacokinetic study of curcumin
A previous pharmacokinetic study of curcumin in mice demonstrated that curcumin could not be detected in plasma after a single oral dose of 75 mg/kg of curcumin. After 4-months administration of 75 and 300 mg/kg of curcumin, plasma levels of curcumin and THC were 0.095 and 0.465 μM and 0.025 and 0.115 μM, respectively (Begum et al., 2008). However, information about the THC CCT251545 analogue receptor rate in either humans or rodents is unavailable to date. Diabetic rats administered THC (80 mg/kg) orally for 45 days showed a significant improvement in erythrocyte membrane bound enzymes and antioxidant defenses, in addition to its anti-hyperglycemic activity (Murugan & Pari, 2007). Moreover, it was found that combined administration of chlorogenic acid (5 mg/kg) and THC (80 mg/kg) could remarkably reduce streptozotocin-induced changes in lipids, lipoproteins, and lipid metabolizing enzymes in diabetic rats (Karthikesan, Pari, & Menon, 2010). In a recent study of high-fat-diet fed C57BL/6 mice, THC (100 mg/kg/day for 10 weeks) markedly reduced hepatic steatosis by 28–37% via a combination of downregulation of lipogenesis, activation of AMP-activated protein kinase (AMPK), and an increase in fatty acid oxidation (Pan et al., 2018). Therefore, the present study might provide information regarding THC dose (100 mg/kg/day) for further study in human (at 6 g divided dose per day). The present study affirmed the antioxidant potential of THC; the lower dose (100 mg/kg) was superior to the higher dose (200 mg/kg) in that it elicited a greater reduction in MDA formation. This result could be due to the overwhelming oxidant-antioxidant capacity at the high THC dose, leading to ROS generation being triggered and/or induction of antioxidant enzymes (Young & Lowe, 2001).
CYP450 oxidative metabolism is a major source of ROS production (Shaik & Mehvar, 2010). NADPH-CYP450 reductase is an enzyme that transfers electron(s) from NADPH to several oxygenases, including CYP450s (Guengerich et al., 2009). CYP450 catalyzes NADPH-mediated oxidation of substrates, leading to the production of hydrogen peroxide, which is further changed to a hydroxyl radical, a powerful free radical in Fenton reactions (Hrycay & Bandiera, 2015b). The sharp increase in NADPH-CYP450 reductase activity in the HFFD mice indicated increased ROS generation, and VitE and THC significantly decreased these values in the HFFD mice. These findings suggested a balancing effect of VitE and THC on the oxidative stress status via the NADPH-CYP450 reductase pathway.
CYP2E1 is a CYP450 isoform that is strongly associated with ROS production (Lu and Cederbaum, 2008, Qi et al., 2013) presumably due to the ease at which electrons are leaked in its catalytic cycle (Gonzalez, 2005). In addition, CYP2E1 is hypothesized to play a key role in the progression of NAFLD, NASH, and AFLD (Jimenez-Lopez and Cederbaum, 2005, Prompila et al., 2008) via the induction of microsomal oxidation, which serves as the main source of free radicals, leading to a decrease in hepatic ATP production and triggering necro-inflammation by pro-inflammatory cytokines (Serviddio, Bellanti, & Vendemiale, 2013). Recent studies have suggested a correlation between CYP2E1 activity and ROS production, as improved levels of antioxidant enzymes and inhibition of CYP450 activity reduced ROS production (Qi et al., 2013, Valencia-Olvera et al., 2014). In the present study, an increase in CYP2E1 expression corresponded with elevated MDA levels in the HFFD mice, indicating the occurrence of oxidative stress. Interestingly, the increase in HFFD-induced CYP2E1 expression was attenuated by VitE and THC. This result corresponded with a previous report on CYP2E1-mediated paracetamol-induced hepatic injury (Zhou et al., 2015). In the previous study, the antioxidant Danshen reduced CYP2E1 activity, decreased oxidative stress, balanced mitochondrial metabolic activity, and attenuated total glutathione depletion (Zhou et al., 2015).