The Tangle of Nuclear Receptors that Controls Xenobiotic Metabolism and Transport: Crosstalk and Consequences

Abstract

The expression of many genes involved in xenobiotic/drug metabolism and transport is regulated by at least three nuclear receptors or xenosensors: aryl hydrocarbon receptor (AhR), constitutive androstane receptor (CAR), and pregnane X receptor (PXR). These receptors establish crosstalk with other nuclear receptors or transcription factors controlling signaling pathways that regulate the homeostasis of bile acids, lipids, glucose, inflammation, vitamins, hormones, and others. These crosstalks are expected to modify profoundly our vision of xenobiotic/drug disposition and toxicity. They provide molecular mechanisms to explain how physiopathological stimuli affect xenobiotic/drug disposition, and how xenobiotics/drugs may affect physiological functions and generate toxic responses. In addition, the possibility that xenosensors may control other signaling pathways opens the way to new pharmacological opportunities.

A link between host plant adaptation and pesticide resistance in the polyphagous spider mite Tetranychus urticae

“…Transcription factors belonging to the nuclear receptor family, the bHLH-PAS family, and the bZIP family are known to be involved in the response to stress and xenobiotics in vertebrates and in insects (60,61). The T. urticae genome harbors at least 700 transcription factors (29), and in a hierarchical clustering analysis (Pearson's centered distance metric, complete linkage rule) with transcription factor expression data, Tomato-5G clustered with MR-VP and MAR-AB and formed a sister clade to Tomato-2h and Tomato-12h.…”

From differential induction of UDP-glucuronosyltransferases in rat liver to characterization of responsible ligand-activated transcription factors, and their multilevel crosstalk in humans

“…Glucocorticoids and other stimuli may activate their response elements in the gtPBREM of UGT1A1. Glucocorticoids have been demonstrated to induce CAR and PXR expression [22]. Hence, activation of different LATFs in the gtPBREM cluster depends upon the presence of activating ligands.…”

“…However, coordinate induction of UGTs by AhR and Nrf2 may also be possible by direct or indirect (via coregulators) interaction between the two transcription factors, as discussed for the control of NQO1 [92]. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 12 liver: rifampicin induces CYP1A1 and 1A2 via AhR in human primary hepatocyte cultures [94], although this finding remains complex and controversial [22]. PXR expression appears to be controlled by PPARα, based on PXR expression and PPREs in the promoter region of PXR [95].…”

Non-coplanar polychlorinated biphenyls (PCBs) are direct agonists for the human pregnane-X receptor and constitutive androstane receptor, and activate target gene expression in a tissue-specific manner

“…In particular, nuclear receptors are associated with the regulation of metabolic homeostasis, through both the action of endosensing receptors such as LXR, FXR and PPAR (Barbier et al, 2002;Mohan and Heyman, 2003), and xenosensing receptors such as PXR and CAR (Bachmann et al, 2004;Pascussi et al, 2008;Wada et al, 2009). Thus, exposure to noncoplanar PCBs may lead to chronic activation of PXR/CAR and potential dysfunction of these metabolic processes.…”