The pregnane X receptor (PXR) is a kind of orphan nuclear receptor activated by a series of ligands. Environmental endocrine disruptors (EEDs) are a wide class of molecules present in the environment that are suspected to have adverse effects on the endocrine system by interfering with the synthesis, transport, degradation, or action of endogenous hormones. Since EEDs may modulate human/rodent PXR, this review aims to summarize EEDs as PXR modulators, including agonists and antagonists. The modular structure of PXR is also described, interestingly, the pharmacology of PXR have been confirmed to vary among different species. Furthermore, PXR play a key role in the regulation of endocrine function. Endocrine disruption of EEDs via PXR and its related pathways are systematically summarized. In brief, this review may provide a way to understand the roles of EEDs in interaction with the nuclear receptors (such as PXR) and the related pathways.

This perspective discusses the role of pregnane xenobiotic receptor (PXR) in drug discovery and the impact of its activation on CYP3A4 induction. The use of structural biology to reduce PXR activity on drug discovery projects has become more common in recent years. Analysis of this work highlights several important molecular interactions, and the resultant structural modifications to reduce PXR activity are summarized. The computational approaches undertaken to support the design of new drugs devoid of PXR activation potential are also discussed. Finally, the SAR of empirical design strategies to reduce PXR activity is reviewed, and the key SAR transformations are discussed and summarized. In conclusion, this perspective demonstrates that PXR activity can be greatly diminished or negated on active drug discovery projects with the knowledge now available. This perspective should be useful to anyone who seeks to reduce PXR activity on a drug discovery project.

Anti-tuberculosis drug-induced hepatotoxicity (ATDH) is a serious adverse drug reaction. Conflicting results have been obtained regarding the associations of nuclear receptor subfamily 1 group I member 2 (NR1I2) gene polymorphisms on susceptibility to ATDH. Therefore, we aimed to evaluate the associations using a systematic review/meta-analysis approach. PubMed, Medline, Cochrane Library, Web of Science and SinoMed databases were searched for all eligible studies from inception to June 10, 2020. Pooled adjusted odds ratios (ORs) with 95% confidence intervals (CIs) were employed to evaluate the strength of the association between the NR1I2 polymorphisms and the risk of ATDH. Subgroup analysis was performed by region of origin, and meta-regression were performed to detect potential sources of heterogeneity. A total of five case-control studies involving 572 cases and 1867 controls were identified. Fourteen SNPs in the NR1I2 gene have been reported, and the most heavily studied SNPs were rs3814055 and rs7643645. The pooled estimates did not exhibit any significant associations between SNPs rs3814055 and rs7643645 and the risk of ATDH (rs3814055: dominant model, OR = 1.00, 95% CI: 0.82-1.22, P = 1.00; recessive model, OR = 1.17, 95% CI: 0.76-1.78, P = .48; rs7643645: dominant model, OR = 1.04, 95% CI: 0.64-1.68, P = .89; recessive model, OR = 0.98, 95% CI: 0.65-1.49, P = .93). Subgroup analysis obtained similar negative results in Chinese patients, and the diagnostic criteria of ATDH may be the source of heterogeneity. Based on the meta-analysis described in this report, we did not observe any association between NR1I2 gene polymorphisms and ATDH susceptibility. However, this conclusion should be interpreted with caution due to the low number of studies and the relatively small sample size.

Current studies have explored the correlation between the single nucleotide polymorphisms (SNPs) of pregnane X receptor (PXR) and cancer risk. However, the findings were conflicting. Hence, we performed a comprehensive review and meta-analysis for these researches to determine the effect of PXR polymorphisms on the risk of cancer. Eligible publications were collected based on a series of rigorous inclusion and exclusion criteria. In consequence, a total of eight case-control studies (from seven citations) covering 11143 cases and 12170 controls were involved in a meta-analysis of ten prevalent PXR SNPs (rs10504191 G/A, rs3814058 C/T, rs6785049 A/G, rs1464603 A/G, rs1523127 A/C, rs2276706 G/A, rs2276707 C/T, rs3732360 C/T, rs3814055 C/T, rs3814057 A/C). The correlations between PXR SNPs and cancer risk were estimated by odds ratios (ORs) with their 95% confidence intervals (95%CIs). The findings demonstrated that rs3814058 polymorphism (CT compared with CC: pooled OR = 1.280, P=6.36E-05; TT compared with CC: pooled OR = 1.663, P=2.40E-04; dominant model: pooled OR = 1.382, P=2.58E-08; recessive model: pooled OR = 1.422, P=0.002; T compared with C: pooled OR = 1.292, P=6.35E-05) and rs3814057 polymorphism (AC compared with AA: pooled OR = 1.170, P=0.036; dominant model: pooled OR = 1.162, P=0.037) were associated with the risk of overall cancer. In stratified analyses, rs3814058 polymorphism was revealed to increase the cancer risk in lung cancer subgroup. In summary, this meta-analysis indicates that the rs3814057 and rs3814058 polymorphisms of PXR gene play crucial roles in the pathogenesis of cancer and may be novel biomarkers for cancer-forewarning in overall population or in some particular subgroups.

OBJECTIVE: Inconsistent results regarding an association between polymorphisms within the Homo sapiens nuclear receptor subfamily 1 group I member 2 (NR1I2) gene and susceptibility to inflammatory bowel disease (IBD) have been reported. A systematic review and meta-analysis was thus undertaken to determine whether NR1I2 gene polymorphisms are associated with an increased risk of IBD.
METHODS: Article retrieval was performed using on-line databases, such as PubMed, Embase, CENTRAL, and WOS. After extracting eligible data, Mantel-Haenszel statistics were applied to calculate the odds radio (OR), 95% confidence interval (95% CI) and P value under a random or fixed-effects model.
RESULTS: A total of seven articles with 4410 IBD subjects and 4028 controls were included. Compared with the control group, no significant increase in IBD susceptibility was observed for the -25385C/T (OR=0.92, 95% CI=0.78∼1.07, P=0.259), -24381A/C (OR=0.96, 95% CI=0.87∼1.06, P=0.378), +8055C/T (OR=1.06, 95% CI=0.97∼1.15, P=0.186), or +7635A/G (OR=0.96, 95% CI=0.87∼1.05, P=0.348) polymorphisms within the NR1I2 gene under the allele model.
CONCLUSIONS: Our meta-analysis failed to demonstrate an association between -25385C/T, -24381A/C, +8055C/T, or +7635A/G polymorphisms within the NR1I2 gene and overall IBD risk. A larger sample size is needed to validate our conclusion.

BACKGROUND: Gut microbiota dysbiosis contributes to the pathogenesis of inflammatory bowel diseases (IBD). Although the microbiota\'s role in IBD pathogenesis, specifically Crohn\'s disease (CD), provides a rationale for antibiotic treatment, antibiotic use in CD remains controversial. Rifaximin, traditionally identified as a nonsystemic bactericidal antibiotic, may be therapeutically beneficial for inducing CD remission.
OBJECTIVE: To examine the role of rifaximin in the management of IBD and its potential mechanisms of action.
METHODS: A literature search using the following strategy: (\'inflammatory bowel disease\' OR \'Crohn\'s\' OR \'ulcerative\'), \'rifaximin\' AND (\'barrier\' OR \'translocation\' OR \'adhesion\' OR \'internalization\' OR \'pregnane X\'), AND \'pregnane X\' AND (\'Crohn\'s\' OR \'ulcerative colitis\' OR \'inflammatory bowel disease\').
RESULTS: In vitro data suggest rifaximin mediates changes in epithelial cell physiology and reduces bacterial attachment and internalisation. In experimental colitis models, rifaximin antagonised the effects of tumour necrosis factor-α on intestinal epithelial cells by activating pregnane X receptor, which inhibits nuclear factor-κB-mediated proinflammatory mediators and induces detoxification genes (e.g. multidrug resistance 1 and cytochrome P450 3A4). Rifaximin also inhibits bacterial translocation into the mesenteric lymph nodes.
CONCLUSIONS: Accumulating evidence suggests that mechanisms of action of rifaximin in IBD may not be limited to direct bactericidal activity; therefore, rifaximin could potentially be redefined as a gut environment modulator.

Cholestasis is a condition in which there is a decrease in or complete cessation of bile flow. Total Parenteral Nutrition (TPN) Cholestasis cases have been on the rise due to the decrease ratio of mortality among premature babies. Using Pubmed, articles were searched using terms in combination: Molecular basis of cholestasis and management. The literature was also retrieved from books attributed to experts in the topic. This article describes the definition, incidence, risk factors, pathogenesis,the molecular basis of hepatobiliary transport, bile acid transporters,cellular regulation, and uptodate and prospective medical Care of TPN Cholestasis. It was found that TPN cholestasis in infants is considered as a major epidemic. Targeting Constitutive androstane receptor and Pregnane X receptor potent agonist will be one of the ultimate goals in inventing new pharmacological agents for the management and treatment of cholestasis related to TPN use. Glutamine, Omega 3 and soybean oil fat appear to have a protective role in the development of TPN cholestasis. However, further studies especially randomized control trials should be conducted.

OBJECTIVE: To survey the evidence for plant-products to modify cytochrome P450 enzyme, and transport protein mediated drug metabolism in renal transplant patients.
METHODS: A literature search was performed to identify \"in vitro\" and \"in vivo\" research on plant-products that might cause overdosage or loss of efficacy of immunosuppressive drugs in transplant patients by the interaction mechanisms already characterized for grapefruit juice and St. John\'s Wort.
RESULTS: The interaction mechanisms of St. John\'s Wort by pregnane X-receptor mediated upregulation of cytochrome-P450 enzyme 3A4 and p-glycoprotein expression and of grapefruit juice by mechanism-based inhibition of intestinal CYP3A4 suggest that many other plant products will likewise cause interactions with drugs because they occupy the same metabolic pathways. The respective research on foods, spices and medicinal herbs is listed in a comprehensive table and weighted according to its strength of evidence to cause clinically relevant interactions.
CONCLUSIONS: Physicians supervising drug-regimes in renal transplant patients should be aware of plant products beyond SJW and GFJ to possibly cause overdosage or failure of drug-treatments by herb-drug interactions.