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  • In conclusion the magnitude of the association between

    2020-02-14

    In conclusion, the magnitude of the association between prenatal exposure to MeHg and child neuropsychological development appears to be modified by polymorphisms in CYP3A7 and CYP3A5 genes in some of the populations studied. These results provide some support for the hypothesis that CYP3A genes may modify the response to MeHg-containing fish exposure during early life development.
    Conflicts of interest
    Acknowledgments
    Introduction Obesity is a complex disorder that affects nearly 1 out of 3 Americans [1] and is considered an epidemic throughout much of the developed world [2,3]. For example, the percent of obese individuals is increasing in Latin America (i.e. Panama 35%, Chili 22%), Europe (Greece 23%, Malta 26%), and the Middle East (United Arab Emirates 34%, Saudi Arabia 36%, Egypt 30%) [2]. In turn, the rates of dyslipidemia, hypertension, diabetes, and other metabolic disorders increased dramatically placing a large burden on our healthcare systems [4,5]. The primary problem is excess food coupled with inactivity. Therefore, healthier food choices and lifestyle changes are common treatment regimens used to control obesity. However, there are multiple internal and external factors that regulate metabolic activity and allocation of dietary lipid and carbohydrate resources [6,7]. Understanding these forces provides targets for initiating dietary and environmental changes and tackling this disease. Many cytochrome P450s (CYPs) are crucial detoxication tachykinin that metabolize drugs [8], environmental chemicals [9], steroids [10] and fatty acids [11], and changes in CYP activity and expression are observed during obesity and diabetic conditions [[12], [13], [14], [15]]. The constitutive androstane receptor (CAR) [16,17] and pregnane X-receptor (PXR) [18] are two nuclear receptors involved in chemical detoxication, and associated with metabolic diseases although possibly in opposing directions. CAR activation alleviates symptoms of obesity and fatty liver disease and murine PXR activation increases obesity [14,15,19], although there are conflicting reports on PXR\'s effects on obesity and insulin resistance [20]. These nuclear receptors are key regulators of CYPs such as Cy2b and Cyp3a subfamily members [18,21,22]. In a world in which we are exposed to numerous environmental toxicants each and every person may show different CYP activity and in turn show differential metabolism of xeno- and endobiotics, including unsaturated fatty acids because of the different diets and chemicals to which they have been exposed [23,24]. Therefore, it is possible that chemicals that modulate CYP activity are obesogens or metabolic disruptors [5,25]. Interestingly, complete loss of hepatic CYP activity in a conditional knockout of P450-oxidoreductase (HRN) caused enlarged livers, and hepatic steatosis, especially after the mice were fed sunflower oil (88% unsaturated fatty acids). In turn, increased hepatic concentrations of unsaturated fatty acids in the HRN mice activated CAR and induced Cyp2b10 and Cyp3a11 providing a putative new role for CAR in the recognition of unsaturated fatty acids and suggests that CYP induction may be a protective mechanism from fatty acid toxicity [19]. Subsequent studies also demonstrated CYP3A induction by fatty acids in human cells [26]. Further, Cyp3a expression and activity is decreased in obese guinea pigs and diabetic humans [27,28], but increased in diabetic mice [15,29]. These results suggest a role for Cyp3a in obesity given that Cyp3a expression changes with diet, loss of hepatic CYPs causes fatty liver disease, and the Cyp3a\'s are the most abundant hepatic CYPs. CYP3A4 accounts for approximately 30–40% of total CYP protein in the human liver and is responsible for the metabolism of more than 60% of the drugs on the market [30]. Cyp3a subfamily members produce a number of epoxidated products of linoleic acid and arachidonic acid in human and rodents. CYP3A4 primarily metabolizes linoleic acid to 11-hydroxy-octadecadienoic acid (11-HODE), and the production of 11-HODE is increased 10X by the CYP3A inducer, dexamethasone, in rats [31]. CYP3A4 oxygenates arachidonic acid to a number of metabolites including 13-, 10-, and 7-hydroxyeicosatrienoic acid (13-HETE, 10-HETE, 7-HETE) [31]. The epoxides formed are stable, but also metabolized by epoxide hydrolases to diols [31]. Whether these epoxides have a specific purpose in the liver is unknown; however, inhibition assays suggest that a Cyp3a-mediated arachidonic acid metabolite is in part responsible for relaxation of arterial endothelium [32]. A Cyp3a and Cyp2j produced metabolite of linoleic acid is a key product in the activation of nociception [33], and CYP3A4 metabolizes the arachidonic acid derivative, anandamide, to a high affinity cannabinoid ligand [[34], [35], [36]]. Thus, Cyp3a metabolizes unsaturated fatty acids for specific functions and disruption of this metabolism by xenobiotics or genetic impairments may have consequences that perturb fatty acid metabolism, distribution, and use [37,38].