Glucose-dependent regulation of pregnane X receptor is modulated by AMP-activated protein kinase

Oladimeji, Peter; Lin, Wenwei; Brewer, Christopher T.; Chen, Taosheng

doi:10.1038/srep46751

Cited by 18 publications

(15 citation statements)

References 68 publications

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“…Rifampicin and isoniazid, which are first-line drugs in antitubercular regimens, have been associated with a human pregnane X receptor (hPXR)-dependent, cholestatic pattern of hepatotoxicity in hPXR transgenic mice. Rifampicin is a well-characterized agonist of hPXR, a nuclear hormone receptor that upregulates the transcription of many genes encoding CYP450 enzymes or xenobiotic transporters Chen, 2016, 2017;Oladimeji et al, 2017;Wang et al, 2014;Watkins et al, 2003). Isoniazid treatment downregulates the level of mouse ferrochelatase (Fech) and upregulates that of d-aminolevulinic acid synthase 1 (ALAS1/Alas1), 2 pivotal enzymes in heme biosynthesis.…”

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confidence: 99%

The Isoniazid Metabolites Hydrazine and Pyridoxal Isonicotinoyl Hydrazone Modulate Heme Biosynthesis

Brewer

Yang

Edwards

et al. 2018

Toxicological Sciences

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In a mouse model, rifampicin and isoniazid combination treatment results in cholestatic liver injury that is associated with an increase in protoporphyrin IX, the penultimate heme precursor. Both ferrochelatase (FECH/Fech) and aminolevulinic acid synthase 1 (ALAS1/Alas1) are crucial enzymes in regulating heme biosynthesis. Isoniazid has recently been reported to upregulate Alas1 but downregulate Fech protein levels in mice; however, the mechanism by which isoniazid mediates disruption of heme synthesis has been unclear. Two metabolites of isoniazid, pyridoxal isonicotinoyl hydrazone (PIH, the isoniazid-vitamin B6 conjugate) and hydrazine, have been detected in the urine of humans treated with isoniazid. Here we show that, in primary human hepatocytes and the human hepatocellular carcinoma cell line HepG2/C3A, (1) isoniazid treatment increases Alas1 protein levels but decreases Fech levels; (2) hydrazine treatment upregulates Alas1 protein and Alas1 mRNA levels; (3) PIH treatment decreases Fech protein levels, but not Fech mRNA levels; and (4) PIH is detected after isoniazid treatment, with levels increasing further when exogenous vitamin B 6 analogs are coadministered. In addition, the PIH-mediated downregulation of human FECH is associated with iron chelation. Together, these data demonstrate that hydrazine upregulates ALAS1, whereas PIH downregulates FECH, suggesting that the metabolites of isoniazid mediate its disruption of heme biosynthesis by contributing to protoporphyrin IX accumulation.

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mentioning

confidence: 99%

The Isoniazid Metabolites Hydrazine and Pyridoxal Isonicotinoyl Hydrazone Modulate Heme Biosynthesis

Brewer

Yang

Edwards

et al. 2018

Toxicological Sciences

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“…Statistical analysis was performed as previously described 17 . Briefly, data from at least three independent replicate experiments were pooled and quantitatively analyzed by analysis of variance (ANOVA) plus Tukey's honest significant difference (HSD) test and by Student's t-test, using GraphPad Prism 7.0 software.…”

Section: Discussionmentioning

confidence: 99%

“…RNA extraction and quantitative real-time PCR. RNA was extracted using Maxwell simplyRNA Kits and a Maxwell 16 Instrument (Promega) as previously described 15,17 . Briefly, RNA concentrations were measured using a NanoDrop 8000 UV-Vis Spectrophotometer (Thermo Fisher Scientific).…”

Section: Methodsmentioning

confidence: 99%

KANSL2 and MBNL3 are regulators of pancreatic ductal adenocarcinoma invasion

Oladimeji

Bakke

Wright

et al. 2020

Sci Rep

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pancreatic ductal adenocarcinoma (pDAc) is one of the most lethal forms of cancer. one major reason for this is that PDAC quickly metastasizes to other organs, thereby making its treatment difficult. The molecular machinery driving pDAc metastasis is still poorly understood. in this study, we applied an unbiased approach using cRiSpR screening to identify genes that strongly regulate invasion (based on an in vitro assessment of their metastatic potential) in PANC-1, a PDAC cell line. Through CRISPR screening, we identified MBNL3 and KANSL2 as strong regulators of invasion in PANC-1 cells. We further validated MBNL3 and KANSL2 as regulators of PANC-1 cell invasion by using the doxycycline-inducible shRnA system. We also showed that MBNL3 and KANSL2 do not affect cell proliferation. Through our efforts, we have established a process to identify genes that regulate cell invasion and can be further investigated as potential targets for therapeutic intervention.Relapse and metastasis of cancers can occur months, years, or even decades after the treatment of the primary tumor, and this can impose a great burden on patients 1 . Metastases of various cancers cause the vast majority of deaths of cancer patients and pose a formidable challenge to oncologists 2 . When metastasis manifests after the surgical removal of a primary tumor, systemic treatments are often used. These treatments include classical chemotherapy, new targeted therapy, immunotherapy or a combination of these therapeutic approaches 2,3 . Despite all efforts on the research and medical fronts to treat metastatic tumors, current therapies often achieve only partial response of metastatic tumors. Continued treatment may keep the residual tumor quiescent only temporarily; however, from the residual cancer cell population, drug-resistant clones ultimately emerge and lead to rapid relapse 4 . Hence, there are currently no effective therapies for treating metastatic cancer and cure rates for patients with metastases is low.Pancreatic cancer, one of the most aggressive malignant neoplasms, is currently the fourth leading cause of cancer-related deaths in Western society. However, by 2030, it is predicted to surpass breast, prostate, and colorectal cancer, and become the second leading cause of cancer-related mortality after lung cancer 5 . According to the estimates by American Cancer Society, the number of people to be diagnosed with pancreatic cancer will be approximately 55,440, and approximately 44,330 people will die of the disease in the USA alone in 2018 6 . According to the most recent estimates of the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program, 52% of all the pancreatic cancers diagnosed between 2007 and 2013 metastasized to distant organs and 29% of them had spread to regional lymph nodes. The 5-year survival rate for all patients with pancreatic cancer during that same period was 8.2% overall for all stages 7 , a rate that is largely a result of the high metastatic potential of pancreatic cancer. Pancreatic ...

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“…Importantly, this low glucosestimulated vaccinia related kinase 1-PXR-PP2C-SGK2 signaling was also observed in mice under fasting conditions, suggesting that this signaling pathway may represent a novel feedback mechanism in response to low glucose that is conserved in both humans and mice. In another study, Oladimeji et al (2017) observed that high glucose increased the expression and activity of PXR in HepG2 cells and that this induction was partially reversed by the activation of AMP-activated protein kinase, suggesting that PXR activity can be modulated by the energy status of the cells.…”

Section: Pregnane X Receptormentioning

confidence: 97%

The Roles of Xenobiotic Receptors: Beyond Chemical Disposition

et al. 2018

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Over the past 20 years, the ability of the xenobiotic receptors to coordinate an array of drug-metabolizing enzymes and transporters in response to endogenous and exogenous stimuli has been extensively characterized and well documented. The constitutive androstane receptor (CAR) and the pregnane X receptor (PXR) are the xenobiotic receptors that have received the most attention since they regulate the expression of numerous proteins important to drug metabolism and clearance and formulate a central defensive mechanism to protect the body against xenobiotic challenges. However, accumulating evidence has shown that these xenobiotic sensors also control many cellular processes outside of their traditional realms of xenobiotic metabolism and disposition, including physiologic and/or pathophysiologic responses in energy homeostasis, cell proliferation, inflammation, tissue injury and repair, immune response, and cancer development. This review will highlight recent advances in studying the noncanonical functions of xenobiotic receptors with a particular focus placed on the roles of CAR and PXR in energy homeostasis and cancer development.

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Glucose-dependent regulation of pregnane X receptor is modulated by AMP-activated protein kinase

Cited by 18 publications

References 68 publications

The Isoniazid Metabolites Hydrazine and Pyridoxal Isonicotinoyl Hydrazone Modulate Heme Biosynthesis

The Isoniazid Metabolites Hydrazine and Pyridoxal Isonicotinoyl Hydrazone Modulate Heme Biosynthesis

KANSL2 and MBNL3 are regulators of pancreatic ductal adenocarcinoma invasion

The Roles of Xenobiotic Receptors: Beyond Chemical Disposition

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