The pregnane X receptor in tuberculosis therapeutics

Shehu, Amina I.; Li, Guangming; Xie, Wen; Ma, Xiaochao

doi:10.1517/17425255.2016.1121381

Cited by 15 publications

(11 citation statements)

References 130 publications

(148 reference statements)

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“…In a subsequent study, the same research group showed that PXR can modulate macrophage drug-efflux transporter expression and activity, compromising the effect of rifampicin in vitro in hMDMs (Fig 2) [92]. Previous studies showed that rifampicin is a potent PXR activator that can induce expression of important metabolizing enzymes [93]. In mice infected with M.tb, the PXR antagonist ketoconazole rescued the activity of rifampicin [92].…”

Section: Pxrmentioning

confidence: 88%

“…Other rifamycin derivatives such as rifapentine and rifabutin do not stimulate PXR regulation of metabolizing enzymes to the same extent as rifampicin [93], and could potentially be used as an alternative to combat PXR-mediated drug non-responsiveness. Further, rifalazil does not induce metabolizing enzymes and no effect on PXR has been observed in animal models [94].…”

Section: Pxrmentioning

confidence: 99%

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Mycobacterium tuberculosis and macrophage nuclear receptors: What we do and don't know

2019

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Nuclear receptors (NRs) are ligand-activated transcription factors that are expressed in a wide variety of cells and play a major role in lipid signaling. NRs are key regulators of immune and metabolic functions in macrophages and are linked to macrophage responses to microbial pathogens. Pathogens are also known to induce the expression of specific NRs to promote their own survival. In this review, we focus on the NRs recently shown to influence macrophage responses to Mycobacterium tuberculosis (M.tb), a significant cause of morbidity and mortality worldwide. We provide an overview of NR-controlled transcriptional activity and regulation of macrophage activation. We also discuss in detail the contribution of specific NRs to macrophage responses to M.tb, including influence on macrophage phenotype, cell signaling, and cellular metabolism. We pay particular attention to PPARγ since it is required for differentiation of alveolar macrophages, an important niche for M.tb, and its role during M.tb infection is becoming increasingly appreciated. Research into NRs and M.tb is still in its early stages, therefore continuing to advance our understanding of the complex interactions between M.tb and macrophage NRs may reveal the potential of NRs as pharmacological targets for the treatment of tuberculosis.

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Section: Pxrmentioning

confidence: 88%

Section: Pxrmentioning

confidence: 99%

Mycobacterium tuberculosis and macrophage nuclear receptors: What we do and don't know

2019

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“…22 PXR has many effects during the treatment of TB as its activation regulates drug metabolizing enzymes and transporters, and this effect has been associated with RIF use. 23 Although Mbatchi and colleagues 24 found no effect of variants in PXR gene on INH exposure, PXR-induced CYPmediated metabolism has been described.…”

Section: Discussionmentioning

confidence: 98%

“…The coadministration of EFV, known to affect RIF and INH exposure, may partially explain this discrepancy as almost all previous studies were conducted in TB mono‐infected subjects: the only study conducted in 56 patients coinfected with HIV/TB reported the effect of SLCO1B1 SNP on RIF concentrations at 2.5 hours, but 95% of enrolled individuals had less common genetic variants . PXR has many effects during the treatment of TB as its activation regulates drug metabolizing enzymes and transporters, and this effect has been associated with RIF use . Although Mbatchi and colleagues found no effect of variants in PXR gene on INH exposure, PXR‐induced CYP‐mediated metabolism has been described.…”

Section: Discussionmentioning

confidence: 99%

The Influence of Pharmacogenetic Variants in HIV/Tuberculosis Coinfected Patients in Uganda in the SOUTH Study

Calcagno

Cusato

Sekaggya-Wiltshire

et al. 2019

Clin Pharma and Therapeutics

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Unsatisfactory treatment outcomes have been reported in patients coinfected with HIV/tuberculosis (TB). The aim of this study was to assess the influence of single‐nucleotide polymorphisms (SNPs) in genes encoding for proteins involved in antitubercular drug disposition or effect. A pharmacogenetic study was conducted in Kampala, Uganda, where all analysis was performed. The impact of SNPs on antitubercular drug exposure, adverse events, and treatment outcomes was evaluated in patients coinfected with HIV/TB receiving treatments for both conditions. In 221 participants, N‐acetyltransferase 2 (NAT2; rs1799930), solute carrier organic anion transporter family member 1B1 (SLCO1B1; rs4149032), and pregnane X receptor (PXR; rs2472677) variants affected isoniazid exposure in multivariate analysis. Most patients were deemed cured (163; 73.8%), yet PXR 63396TT carriers had a higher probability of death (P = 0.007) and of worsening peripheral neuropathy (P = 0.018). In this exploratory study in Ugandan patients coinfected with HIV/TB, genetic variants in PXR, SLCO1B1, and NAT2 were moderately associated with isoniazid exposure, whereas PXR 63396TT carriers showed worse outcomes.

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“…Therefore, a balance between PXR transcriptional activation and repression is needed, not only to maintain appropriate physiologic levels of endogenous chemicals but also to achieve optimal therapeutic efficacy with fewer drug‐induced toxicities. Because of its important role in regulating drug efficacy and drug toxicity, as well as its emerging roles in other physiologic and pathologic processes such as energy metabolism and metabolic diseases, infectious diseases, cancer, and inflammatory bowel disease (IBD), as briefly discussed in Sections to , PXR has become an attractive therapeutic target . However, PXR is notorious for promiscuously binding structurally diverse chemicals, including clinical drugs, environmental toxins, and endogenous metabolites, making it a challenging therapeutic target partly because of the perceived difficulty of studying its structure‐activity relationship .…”

Section: Introductionmentioning

confidence: 99%

Strategies for developing pregnane X receptor antagonists: Implications from metabolism to cancer

Chai

Wright

Chen

2019

Medicinal Research Reviews

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Pregnane X receptor (PXR) is a ligand-activated nuclear receptor (NR) that was originally identified as a master regulator of xenobiotic detoxification. It regulates the expression of drug-metabolizing enzymes and transporters to control the degradation and excretion of endobiotics and xenobiotics, including therapeutic agents. The metabolism and disposition of drugs might compromise their efficacy and possibly cause drug toxicity and/or drug resistance. Because many drugs can promiscuously bind and activate PXR, PXR antagonists might have therapeutic value in preventing and overcoming drug-induced PXR-mediated drug toxicity and drug resistance. Furthermore, PXR is now known to have broader cellular functions, including the regulation of cell proliferation, and glucose and lipid metabolism. Thus, PXR might be involved in human diseases such as cancer and metabolic diseases. The importance of PXR antagonists is discussed in the context of the role of PXR in xenobiotic sensing and other disease-related pathways. This review focuses on the development of PXRantagonists, which has been hampered by the promiscuity of PXR ligand binding. However, substantial progress has been made in recent years, suggesting that it is feasible to develop selective PXR antagonists. We discuss the current status, challenges, and strategies in developing selective PXR antagonists. The strategies are based on the molecular mechanisms of antagonism in related NRs that can be applied to the design of PXR antagonists, primarily driven by structural information.The nuclear receptor (NR) pregnane X receptor (PXR, NR1I2) plays a prominent role in the detoxification system that humans and other organisms utilize to eliminate endobiotics such as steroid hormones, bile acids, and glucose and xenobiotics such as therapeutic agents. Upon the binding of a ligand, PXR transcriptionally upregulates the expression of drug-metabolizing enzymes and transporters, leading to the metabolism and, ultimately, clearance of endobiotics and xenobiotics. These chemicals undergo biotransformation and disposition through a series of processes comprising oxidation and conjugation reactions (involving cytochrome P450 enzymes [CYPs], such as CYP3A4, UDP-glucuronosyltransferases, and glutathione-S-transferases, sulfotransferases) and active efflux (involving the transporter proteins multidrug resistance proteins and multidrug resistance-associated proteins). [1][2][3][4] PXR and the detoxification system represent a double-edged sword: Although detoxification serves as a beneficial protection mechanism against toxic compounds, it also compromises therapeutic outcomes by decreasing drug efficacy and possibly inducing drug toxicity and resistance. Therefore, a balance between PXR transcriptional activation and repression is needed, not only to maintain appropriate physiologic levels of endogenous chemicals but also to achieve optimal therapeutic efficacy with fewer drug-induced toxicities. Because of its important role in regulating drug efficacy and drug toxicity, as wel...

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The pregnane X receptor in tuberculosis therapeutics

Cited by 15 publications

References 130 publications

Mycobacterium tuberculosis and macrophage nuclear receptors: What we do and don't know

Mycobacterium tuberculosis and macrophage nuclear receptors: What we do and don't know

The Influence of Pharmacogenetic Variants in HIV/Tuberculosis Coinfected Patients in Uganda in the SOUTH Study

Strategies for developing pregnane X receptor antagonists: Implications from metabolism to cancer

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