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  • In vivo study showed that the CYP A activity

    2021-01-11

    In vivo study showed that the CYP3A activity was increased, when morroniside (10, 30 and 90 mg/kg, i.g.) was daily for seven consecutive days. Further, RT-PCR analysis showed that the induction of mRNA Pyronaridine Tetraphosphate by morroniside (10, 30 and 90 mg/kg, i.g.) was 1.13-, 1.43- and 1.79-fold higher, respectively, relative to the control. And the western blot analysis showed that the induction of protein expression by morroniside was 1.23-, 1.41- and 1.44-fold higher, respectively. The results were well correlated with the observed CYP3A activity increase. The observed AUC0–6h of midazolam in morroniside treated rats also indicated that morroniside indeed enhanced the CYP3A activity. The dexamethasone treated rat model was widely used for induction of CYP3A activity (25). In this model, as plasma concentration of midazolam depended upon CYP3A activity, the observed effects of dexamethasone on the AUC of midazolam were well in accordance with the earlier report (26). The above findings showed that morroniside treatment could induce the CYP3A activity. So, it needed to pay attention to the drug–drug interactions.
    Conclusions
    Conflicts of interest
    Acknowledgements
    Introduction Methylmercury (MeHg) is a ubiquitous environmental toxicant that derives from both natural sources and human activity (World Health Organization (WHO), 2007a). MeHg is present in almost all aquatic species as a result of the methylation of inorganic mercury by microorganisms present in sediments (Parks et al., 2013) and subsequent bioaccumulation up the food chain. Human exposure occurs almost exclusively through consumption of fish and marine mammals. About 95% of the MeHg ingested from fish is absorbed into the bloodstream and readily crosses the placental and blood–brain barrier where it poses the greatest risk for developmental neurotoxicity (World Health Organization (WHO), 2007b). Several epidemiologic studies have examined the consequences of prenatal MeHg exposure from maternal consumption of fish or seafood on child cognitive and motor development and have found conflicting results, with some studies reporting adverse associations and others finding no influence of exposure on developmental outcomes (Davidson et al., 2008, Grandjean et al., 1997, Llop et al., 2012, Valent et al., 2013). Methodological differences, co-exposures to several environmental pollutants and nutritional factors may have contributed to this observed heterogeneity in effect estimates. In addition, it has been postulated that individual and population genetic differences may also influence MeHg toxicity (Llop et al., 2015, National Research Council, 2000). Only a few studies have addressed the role of genetics in MeHg toxicity, with most studies based on adult populations (Llop et al., 2015). Candidate genes in the glutathione (GSH) metabolism pathway have been primarily considered since the formation of MeHg-GSH conjugates are thought to be key to excretion (Ballatori and Clarkson, 1983, Barcelos et al., 2013, Custodio et al., 2004, Engstrom et al., 2008, Engström et al., 2016, Gundacker et al., 2007). However, results have been inconsistent regarding the modifying role of these genes. In an attempt to identify MeHg tolerance and susceptibility genes through an unbiased transcriptomic screen using developing neural tissue of Drosophila several members of the Cytochrome p450 (CYPs) family were resolved as gene candidates (Mahapatra et al., 2010). CYPs are a superfamily of enzymes involved in oxidative metabolism of xenobiotics. Genetic polymorphism in these drug metabolizing enzymes is considered to be a major contributor to individual susceptibility to environmental, chemical and drug toxicity (Johansson and Ingelman-Sundberg, 2011). Functional studies in Drosophila showed that ectopic expression of the Drosophila CYP6g1 gene, as well as expression of its human homolog CYP3A4, in flies, conferred tolerance to developmental MeHg toxicity (Rand et al., 2012). The human CYP3A subfamily is comprised of four distinct genes: CYP3A4, CYP3A5, CYP3A7 and CYP3A43, which are located in close proximity on chromosome 7. CYP3A4, CYP3A5, CYP3A7 are predominantly expressed in the liver, kidney and gut tissues where they catalyze drug and xenobiotic metabolism (Anzenbacher and Anzenbacherová, 2001). CYP3A enzymes are also essential for the synthesis of endobiotics, such as sex hormones and fatty acids (Hasler, 1999, Zanger and Schwab, 2013) that are crucial in nervous system development. In a developmentally regulated process CYP3A7 is preferentially expressed in human fetal liver which is replaced with CYP3A4 expression postnatally (Hakkola et al., 1998). The expression and function of CYP3A genes in extra-hepatic tissues are less well characterized, nonetheless there is evidence for CYP3A transcripts in developing brain (https://www.ebi.ac.uk/gxa/home). While a direct role of CYPs in MeHg metabolism remains under investigation (Rand et al., unpublished observations), early studies have shown an ability of liver microsomes to biotransform MeHg to inorganic Hg in vitro (Nakayama, 1976). Since MeHg de-methylation is recognized as a rate-limiting step in MeHg elimination (Farris et al., 1993, Smith et al., 1994), and correspondingly dictates the body burden of MeHg, a potential enzymatic role for CYPs in mediating MeHg metabolism presents an attractive hypothesis to explore in population based studies.