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    • Xenobiotic metabolizing enzymes are classified as

    2022-07-14

    Xenobiotic metabolizing enzymes are classified as being phase I, phase II and transporter enzymes, with phase I enzymes metabolizing lipophyllic xenobiotics to make them more polar so that the phase II enzymes can perform the necessary conjugation reactions that afford elimination. Although the phase II enzymes more commonly interact with the product of phase I enzyme metabolism, they can also interact directly with the more polar xenobiotics, eventually eliminating metabolites from the body using both passive and U 18666A mechanisms. In effect, most xenobiotics are cleared using multiple enzymes and pathways but for a great deal of xenobiotics, the exact enzyme and pathways utilized are yet to be determined. Both developmental age and genetics have a role in determining susceptibility to the effects of particular xenobiotics and just which metabolic reactions dominate in a given individual will involve relative chemical dose exposure alongside enzyme affinity and enzyme and cofactor availability (Croom, 2012). It is significant regulation, at gene expression level, by members of the nuclear receptor (NR) family of ligand-modulated transcription factors (Wallace and Redinbo, 2013) that enables the above-mentioned catalytic systems to perform processes such as oxidation, conjugation and transport of potentially deleterious xenobiotic and endobiotic compounds. NRs activated by a variety of endo- and exogenous chemicals are also required for the induction and suppression of drug-metabolism pathways and are closely involved in the pathogenesis of human diseases (e.g. cancer, diabetes, inflammatory disease, metabolic disease and liver disease). Glucocorticoid Receptors (GR), although not sharing the degree of promiscuous xenobiotic binding activity seen with the NR, pregnane X receptor (PXR) and to a lesser extent the constitutive androstane receptor (CAR), nevertheless play important roles in the regulation of metabolic gene expression involving xenobiotics.
    Background on glucocorticoids Glucocorticoids (GC), the natural ligand of the Glucocorticoid Receptor (GR) are cholesterol-derived lipophilic steroid hormones produced by the adrenal glands. Endogenously-produced glucocorticoids include cortisone (the predominant form in humans), cortisol and corticosterone (rodents) (Biddie et al., 2012). Hormonal levels of GC follow a circadian rhythm with highest serum cortisone levels occurring in the morning shortly after waking and lowest around midnight (Chan and Debono, 2010). Regulation of hormone secretion is achieved by way of negative feedback involving the hypothalamic-pituitary-adrenal (HPA) axis. Essentially, the HPA axis receives input from circadian oscillators (pacemaker cells) situated in the supra-chiasmic nucleus (SCN) of the hypothalamus. The pacemaker controls circadian release of corticotrophin-releasing hormone (CRH) from the cells of the paraventricular nucleus in the same structure. CRH, also secreted in response to physical and emotional stressors, brings about the release of adrenocorticotrophic hormone (ACTH) from the pituitary corticotrophs, which in turn stimulates the release of adrenal cortisol. Rising serum cortisol levels serve to inhibit further CRH and ACTH release in a classical feedback loop (Chan and Debono, 2010). Evidence also exists for pacemaker cells, located in peripheral tissues, as having a role in supporting circadian rhythm (Balsalobre et al., 2000). In humans, the availability of endogenous GC is also regulated by serum levels of corticosteroid-binding globulin (CBG), and by tissue levels of 11β-hydroxysteroid dehydrogenase (11β-HSD) isozymes that catalyze the interconversion of cortisol and cortisone (van Uum et al., 1998). Endogenous production of GC is critical in maintaining both basal and stress-related homeostasis through the regulation of growth, development, metabolism, reproduction, blood pressure and circulation, the immune and inflammatory responses, water and electrolyte homeostasis, cognition and behaviour (Nicolaides et al., 2010, Nicolaides et al., 2015).