Xenobiotics sensors

Of all N Rs involved in xenobiotics metabolism induction, PX R is the most prominent one. PXR functions as a xenobiotic sensor and is activated by a large variety of chemically diverse compounds, for example lovastatin, nifedipine, rifampicin, SR12813, troglitazone or hyperforin (Chart 14.3), many of them standard therapeutic agents for common diseases [20-25]. 

Burk O, Koch I, Raucy J, et al. The induction of cytochrome P450 3A5 (CYP3A5) in the human liver and intestine is mediated by the xenobiotic sensors pregnane X receptor (PXR) and constitutively activated receptor (CAR). J Biol Chem 2004 279(37) 38379-38385. 

Further characterization of the interactions with other signalling pathways and functional links to other hormonal, metabolic and xenobiotic sensors represents a very challenging issue. A refined picture of these networks would provide a better understanding of liver pathologies, including those related to the metabolic syndrome. 

Microorganisms capable of degrading polychlorinated biphenyls (PCB) have been isolated and used in biosensors to determine these important group of xenobiotics. Table 13 shows that the sensors reacted to PCB, but the sensitivity and specificity was not sufficient for the specific determination of PCB for all used microorganisms [119-121]. 

Microbial sensors are less suitable for the determination of individual analytes. However, in some cases, specific metabolic pathways are used, allowing microbial sensors to be more selective for those xenobiotic compounds, which are not detectable with simple enzyme reactions, e.g., aromatic compounds and... 

Beyersdorf-Radek B, Riedel K, Nemnann B, ScheUer F, Schmid RD (1992) Development of microbial sensors for determination of xenobiotics. GBF Monographs 17 55-60... 

PERI). The members of this protein family tend to act as environmental sensors. For instance, while the AhR mediates responses to xenobiotics, HIFl-Alpha mediates responses to low oxygen levels, and PERI and MOP3 are involved in the circadian rhythmicity, which, in part, is a response to light. 

Receptors/sensors involved in regulation of xenobiotic-metabolizing enzymes... 

As illustrated in Fig. 1, methionine synthase is positioned at the intersection between transsulfuration and methylation pathways. As a consequence, its level of activity exerts control over cellular redox status, since it determines the proportion of HCY that will be diverted toward cysteine and GSH synthesis. Methionine synthase activity is exceptionally sensitive to inhibition during oxidative stress, primarily because its cobalamin cofactor is easily oxidized (Liptak and Brunold, 2006). This allows methionine synthase to serve as a redox sensor, lowering its activity whenever the level of oxidation increases, until increased GSH synthesis brings the system back into balance. Electrophilic compounds, such as oxygen-containing xenobiotic metabolites, also react with cobalamin, inactivating the enzyme and increasing diversion of HCY toward GSH synthesis (Watson et al., 2004). Thus, methionine synthase is a sensor of both redox and xenobiotic status. 

Phase II drug metabolism was initially considered as a constitutive detoxification process occurring specifically in the liver. However, an increasing body of evidences generated during the last decade clearly established that conjugating enzymes are also expressed in numerous extrahepatic tissues, and that their expression is tightly controlled by transcription factors that function as sensors for endo- and xenobiotics. Furthermore, the important role that these enzymes exert in the control of hormones... 

The PAS domain transcriptional factor AhR is a nonnuclear receptor xenobiotic receptor. In the early 1990s, the AhR and its partner Ah receptor nuclear translocator (Arnt) protein were identified as a transcriptional sensor mediating the induction of CYP1A and 1B1 genes by dioxin and related polycyclic aromatic hydrocarbons [62, 63],... 

In addition to PXR and CAR, several other nuclear receptors, such as vitamin D receptor (VDR), hepatocyte nuclear factor 4a (HNF4a), peroxisome proliferator-activated receptors (PPARs), and farnesoid X receptor (FXR), have also been implicated in the regulation of xenobiotic enzymes and transporters [9-12], More recently, results from our lab have shown that the liver X receptor (LXR), a previously known sterol sensor, can also regulate the expression of phase II SULTs, such as the bile acid detoxifying hydroxysteroid sulfotransferase Sult2a9/2al [13] and the estrogen sulfotransferase (Est/Sultlel) [14],... 

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