No abstract

Xenobiotic and drug metabolism and transport are managed by a large number of genes coordinately regulated by at least three nuclear receptors or xenosensors: aryl hydrocarbon receptor (AhR), constitutive androstane receptor (CAR, NR1I3), and pregnane X receptor (PXR, NR1I2). Initially characterized as xenosensors, it is now evident that CAR and PXR also trigger pleiotropic effects on liver function. Recent studies have shown the existence of crosstalk between xenosensors and other nuclear receptors or transcription factors controlling endogenous signaling pathways which regulate physiological functions. This review is focused on recent observations showing that activation of CAR and PXR alters lipid metabolism, glucose homeostasis, and inflammation by interfering with HNF4alpha, FoxO1, FoxA2, PGC1alpha, or NFkB p65. Such crosstalks explain clinical observations and provide molecular mechanisms allowing understanding how xenobiotics and drugs may affect physiological functions and provoke endocrine disruptions.

Therapeutic drug monitoring of IFX strongly predicts the likelihood of achieving MH following IFX dose intensification in both CD and UC.

This meta-analysis clearly establishes an association between 6-thioguanine nucleotides levels and clinical remission rates in patients with inflammatory bowel disease and explains the heterogeneity of results among selected studies. The lack of standardization in 6-thioguanine nucleotides assays is responsible for recent contradictory results. Whether therapeutic drug monitoring of thiopurines should be systematically used in clinical practice in inflammatory bowel disease to improve disease outcomes will require further investigation.

The pregnane X receptor (PXR) initially isolated as a nuclear receptor regulating xenobiotic and drug metabolism and elimination, seems to play an endobiotic role by affecting lipid homeostasis. In mice, PXR affects lipid homeostasis and increases hepatic deposit of triglycerides. In this study, we show that, in human hepatocyte, PXR activation induces an increase of de novo lipogenesis through the up-regulation of S14. S14 was first identified as a thyroid-responsive gene and is known to transduce hormone-related and nutrient-related signals to genes involved in lipogenesis through a molecular mechanism not yet elucidated. We demonstrate that S14 is a novel transcriptional target of PXR. In addition, we report an increase of fatty acid synthase (FASN) and adenosine triphosphate citrate lyase genes expression after PXR activation in human hepatocyte, leading to an increase of fatty acids accumulation and de novo lipogenesis. RNA interference of the expression of S14 proportionally decreases the FASN induction, whereas S14 overexpression in human hepatic cells provokes an increase of fatty acids accumulation and lipogenesis. These results demonstrate for the first time that xenobiotic or drug-activated PXR promote aberrant hepatic de novo lipogenesis via activation of the nonclassical S14 pathway. In addition, these data suggest that the up-regulation of S14 by PXR may promote aberrant hepatic lipogenesis and hepatic steatosis in human hepatocytes. (HEPATOLOGY 2009;49:2068-2079 L ipid homeostasis is achieved by complex physiological mechanisms. Disruptions of lipid formation and catabolism have been implicated in various metabolic diseases such as obesity and diabetes. Hepatic lipid homeostasis is tightly maintained by balanced lipid synthesis, catabolism (␤-oxidation), and uptake/secretion. The liver is a major organ for lipogenesis and expresses high levels of lipogenic enzymes, such as fatty acid synthase (FASN), adenosine triphosphate citrate lyase, and stearoyl-CoA desaturase-1. Several receptors have been implicated in lipid homeostasis, such as the liver X receptor alpha and beta isoforms (LXR␣ and LXR␤ 1 ) or thyroid hormone receptor (TR 2 ). The effect of LXR on lipogenesis involves both direct and indirect mechanisms. LXR/retinoid X receptor (RXR) heterodimers bind lipogenic gene promoters, such as FASN, or regulate lipogenic gene expression by controlling levels of sterol regulatory element binding protein (SREBP)-1c, a transcriptional factor known to regulate the expression of a battery of lipogenic enzymes. [3][4][5] In addition, thyroid hormone (T3) is known to regulate hepatic lipogenesis after binding to TR, which binds to the target DNA sequence thyroid response element (TRE), leading to an increased transcription of several genes involved in lipogenesis. 6,7 The pregnane X receptor (PXR), initially isolated as a nuclear receptor regulating xenobiotic and drug metabolism and elimination, 8 plays an endobiotic role by affect-

The presence of AAA is associated with a higher risk of loss of clinical response to adalimumab, whereas high TRA is associated with greater clinical response rates in CD. More data are needed in ulcerative colitis.

Macrophages represent major cellular targets of various drugs, especially antibiotics and anti-viral drugs. Factors that may govern intracellular accumulation of drugs in these cells, especially those related to activity of drug transporters, are consequently likely important to consider. The present study was therefore designed to extensively characterize expression of solute carrier (SLC) and ATP-binding cassette (ABC) transporters in primary human macrophages generated from blood monocytes. Using quantitative polymerase chain reaction assays, these cells were found to exhibit very high or high levels of mRNA expression of concentrative nucleoside transporter (CNT) 3, equilibrative nucleoside transporter 3, monocarboxylate transporter (MCT) 1, MCT4, peptide/histidine transporter (PHT) 1, PHT2, organic anion transporting polypeptide transporter 2B1 and ABC pumps multidrug resistance protein (MRP) 1/ABCC1 and MRP3/ABCC3. By contrast, other transporters, including the efflux pump ABCB1/P-glycoprotein, were found at lower levels or were not expressed. Concomitantly, human macrophages displayed notable uptake of the MCT substrate lactate and of the CNT substrate uridine and also exhibited cellular efflux of the MRP substrate carboxy-2',7'-dichlorofluorescein. Such a functional expression of these transporters has likely to be considered with respect to cellular pharmacokinetics of drugs targeting macrophages.

The biochemical variations induced in human primary hepatocyte cultures by reference activators of xenoreceptor CAR (NR1I3) and PXR (NR1I2), i.e., rifampicin, phenobarbital, and 6-(4-chlorophenyl)imidazo[2,1-b] [1,3]thiazole-5-carbaldehyde O-3,4-dichlorobenzyl) oxime (CITCO), were investigated using a global metabonomics approach. Cultured human hepatocytes were treated with the three drugs before analysis of intracellular and extracellular media by ultra performance liquid chromatography/time-of-flight-mass spectrometry (UPLC/TOF-MS) technique, in order to list endogenous compounds potentially related to a PXR or CAR induction mechanism and to identify drug metabolites related to each treatment. The emphasis was put on the quality of the analytical data (dilution/filtration strategy before data processing) and on the appropriate pattern recognition techniques. In cellular media, the most significant variations seen in the data are not related to the treatments but to the source of hepatocytes, illustrating the importance of the genetic and/or environmental background in human liver experiments. However when applying classical multivariate statistical approaches (principal component analysis (PCA) and orthogonal partial least squares (O-PLS)), the statistical weight due to drug metabolites, present only in the treated groups, hinders the interpretation because of their predominance compared to most of the changes seen in endogenous metabolites. A new statistical approach, called shared and unique structure (SUS) plot, enabling the comparison of different treatments having the same control has been applied, allowing separation of clearly exogenous variables (drug metabolites) from endogenous biomarkers. Endogenous variables (either up- or down-regulated) have been attributed specifically to the impact of rifampicin (PXR ligand), CITCO (CAR ligand), and phenobarbital (CAR and PXR activator) on the biological regulation pathways of the hepatocytes. This global approach coupled to a statistical pretreatment of the data, enabling the separate capture of both drug related and drug induced biomarkers, represents a powerful technique for future mechanistic studies using cellular tools.