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Xenobiotic regulation of Phase I and Phase II metabolism enzymes : beyond the Ah receptor paradigm


Phase I and Phase II metabolizing enzymes assist in the removal of endogenous and exogenous chemicals by increasing their hydrophilicity and thereby facilitating excretion from the body. One of the primary responses to exposure to the prevalent environmental carcinogens polycyclic and halogenated aromatic hydrocarbons (PAH/HAH) is activation of the aryl hydrocarbon (Ah) receptor to increase expression of the Phase I enzyme cytochrome P450 1A1 (CYP1A1) and the Phase II enzyme UDP- glucuronosyltransferase 1A1 (UGT1A1). In addition to these carcinogens, humans are exposed to many other substances which when combined, present a more complicated mechanism of carcinogenesis that may not be readily identified using the classically understood Ah receptor pathway. Using two different chemical induction models, we demonstrate further levels of complexity of Ah receptor-mediated transcription. First, I saught to elucidate the mechanism of As³⁺ inhibition of TCDD-mediated CYP1A1 induction. As³⁺ interferes with TCDD/Ah receptor-mediated recruitment of basal transcription factors to the CYP1A1 promoter but does not impair the basic functionality of the Ah receptor. The second model examined was induction of UGT1A1 by a new class of Ah receptor activators, the flavonoids. The flavonoid chrysin is shown to be a more effective inducer of the UGT1A1 gene than the most potent Ah receptor ligand, TCDD. We demonstrate that chrysin, as an Ah receptor ligand, induces CYP1A1 expression. In contrast, the Ah receptor is minimally involved in chrysin induction of UGT1A1 expression. This suggests that the role of the Ah receptor differs in accordance with the type of ligand and target gene. In addition to Ah receptor regulation, nuclear receptors play an important role in UGT1A inducibility. As many of these receptors play key roles in disease, the effect of high fat diet-induced type 2 diabetes on UGT1A expression was examined in Tg-UGT1 mice. Unexpectedly, Tg-UGT1 while increasing adiposity do not develop the expected phenotype of hyperinsulinemia and glucose and insulin intolerance suggesting that overexpression of UGT1A proteins is protective against the early phases of type 2 diabetes. Paradoxically, human UGT1A expression was down-regulated in high fat diet mice indicating that adiposity negatively impacts on UGT1A expression

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