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  • A cocktail approach can detect the activities

    2019-07-11

    A cocktail approach can detect the activities of multiple CYP 450 isoforms following administration of multiple CYP-specific substrates in a single experiment. Caffeine, losartan, omeprazole, dextromethorphan and midazolam are often used as substrates in “cocktail probes” of human cytochrome CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4, respectively (Ryu et al., 2007). The object of our study was to assess the DDI magnitude of SLT and identify the attribution of its herbal components on the overall effect of SLT with respect to five major CYP450 isoforms in rats.
    Materials and methods
    Result and discussion
    Conclusion
    Conflict of interests
    Acknowledgments This study was financially supported by “Major New Medicine Project” in Megaprojects of Science Research of China (No. 2009ZX09502-006), the National Natural Science Foundation of China (30701101) and the National Basic Research Program of China (973 program, 2015CB554400)
    Introduction Overconsumption of a hypercaloric diet high in fat and/or fructose leads to metabolic dysregulation and the associated features of metabolic syndromes, including body weight gain, lipid dysregulation, and elevation of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels (Sobrecases et al., 2010). There are several lines of evidence indicating that this type of diet enhances the production of free radicals and lowers antioxidant levels, resulting in a redox imbalance and oxidative stress (Delbosc et al., 2005, Jarukamjorn et al., 2016). We previously reported that mice receiving a high-fat and high-fructose diet (HFFD) exhibited signs of oxidative stress that resulted from an increase in lipid peroxidation levels and a decrease in glutathione stores over the long term. Furthermore, HFFD-fed mice exhibited increased transcription of TPEN encoding antioxidant enzymes, including superoxide dismutase, catalase, and glutathione peroxidase, within 4 weeks as a result of excessive free radical production (Jarukamjorn et al., 2016). Phase I oxidation and phase II conjugation are two major reactions involved in the biotransformation of drugs and xenobiotics. Microsomal cytochrome P450 enzyme (CYP450) plays a major role in catalyzing phase I reactions of clinical drugs and environmental substances, modifying their functional groups to create more polar and/or less toxic metabolites (Zanger & Schwab, 2013). However, the CYP450-mediated oxidative metabolism of substances may generate toxic electrophiles and reactive oxygen species (ROS). For example, CYP2E1 activity is associated with the progression of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) resulting from increased ROS and oxidative stress (Lu & Cederbaum, 2008). Phase II conjugation functions to eliminate toxic electrophiles and ROS generated from phase I reactions and to prevent an increase in oxidative stress. UDP-glucuronosyltransferase (UGT) and glutathione-S-transferase (GST) are two important enzymes in phase II metabolism, conjugating glucuronide and glutathione to xenobiotics, respectively, to facilitate their excretion (Markey, 2012). NAD(P)H:quinone oxidoreductase (NQO) is an important phase II enzyme in the liver, catalyzing the two-electron reduction in quinones to hydroquinones and preventing the one-electron reduction in quinones to semiquinone radicals by CYP450 (Zhu & Li, 2012). The concept of using antioxidants to balance unfavorable redox states induced by disease-related oxidative stress has been widely published (Afzal et al., 2015, Vera-Ramirez et al., 2013). Tetrahydrocurcumin (THC) is a metabolite of curcumin, a major active compound in turmeric (Curcuma longa), that has great potential as an antioxidant (Muthumani & Miltonprabu, 2015). THC has been shown to normalize AST and ALT levels in rats following arsenic-induced oxidative damage and to benefit metabolic conditions through the recovery of cholesterol, free fatty acid, triglyceride, and phospholipid levels (Muthumani and Miltonprabu, 2015, Pari and Murugan, 2007). Moreover, THC has been demonstrated to balance CYP450 patterns in mice fed a HFFD (Jearapong, Chatuphonprasert, & Jarukamjorn, 2015). Thus, THC is a promising candidate to develop as a dietary supplement due to its antioxidant activity and its positive effect on metabolic conditions. The pathway by which THC reduces oxidative stress through modification of drug-metabolizing enzymes is still not completely understood. Therefore, the current study aimed to investigate how HFFDs influence oxidative stress-related modification of phase I and phase II drug-metabolizing enzyme systems, including CYP450, GST, UGT, and NQO, and whether THC affects the modifications they generate.