Regulation of CYP450 and drug transporter mediated by gut microbiota under high-altitude hypoxia

Bai, Xue; Yang, Jing; Liu, Guiqin; Zhu, Junbo; Wang, Qian; Gu, Wenqi; La, Linli; Li, Xiangyang

doi:10.3389/fphar.2022.977370

Cited by 6 publications

(4 citation statements)

References 36 publications

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“…For example, they both participate in the regulation of bile acid metabolism. PXR has important downstream factors in the liver cytochrome P450 3A4(CYP3A4, Cyp3a11 in mice) and cytochrome P450 17A1 (Cyp17a1), which are key metabolic enzymes in the body 30,31 . PXR initiates CYP3A4 transcription and alters the metabolic rate by binding to specific ligands, such as some drugs 10,32,33,34 .…”

Section: Discussionmentioning

confidence: 99%

“…PXR has important downstream factors in the liver cytochrome P450 3A4(CYP3A4, Cyp3a11 in mice) and cytochrome P450 17A1 (Cyp17a1), which are key metabolic enzymes in the body. 30,31 PXR initiates CYP3A4 transcription and alters the metabolic rate by binding to specific ligands, such as some drugs. 10,32,33,34 Previous studies in our laboratory have found that PXR regulates Cyp17a1.…”

Section: Discussionmentioning

confidence: 99%

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HNF4α improves hepatocyte regeneration by upregulating PXR

Qiu,

Pan,

Cui

et al. 2024

The FASEB Journal

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Hepatocyte nuclear factor 4 alpha (HNF4α) and the pregnane X receptor (PXR) are involved in hepatocyte regeneration. It is not clear whether HNF4α is involved in hepatocyte regeneration through the regulation of PXR. This study aims to explore the regulatory relationship between HNF4a and PXR, and whether it affects hepatocyte regeneration. A mouse PXR gene reporter and an HNF4α overexpression plasmid were constructed and transfected into mouse hepatoma cells (Hepa1‐6). Overexpression of HNF4α, detection of the PXR gene reporter fluorescence value, PXR gene, and protein expression analysis were conducted to explore the regulatory relationship between HNF4α and PXR. Apoptosis and cell cycle data were measured to verify whether HNF4α is involved in hepatocyte regeneration through PXR. The luciferase gene reporter assay results indicated when HNF4α was overexpressed, the fluorescence value of the PXR gene reporter was higher than that in the control at 24 h. With increasing HNF4α expression, the PXR gene and protein expression increased, indicating that HNF4α binds to the PXR promoter and upregulates PXR expression. Apoptosis and cell cycle analysis results demonstrated that when the expression of HNF4α increased, the expression of PXR increased, the apoptosis rate decreased, and the proliferation rate increased. Meanwhile, when the upward trend of PXR gene expression was inhibited by ketoconazole, the proliferation rate decreased. By inhibiting HNF4α and creating a partial hepatectomy (PHx), we demonstrated that HNF4α can upregulate PXR to promote liver regeneration in vivo. Therefore, HNF4α is shown to improve hepatocyte regeneration by upregulating PXR, which provides a reference for future research on the combined application of drugs for the treatment of liver injury.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

HNF4α improves hepatocyte regeneration by upregulating PXR

Qiu,

Pan,

Cui

et al. 2024

The FASEB Journal

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“…For example, the current study ignores the role of drug metabolism on bioavailability. Previous studies have demonstrated the capacity for the gut microbiome to modulate hepatic cytochrome P450 (CYP450) enzyme activities [41,42]. In the context of lurasidone, this presents another avenue of pharmacokinetic modulation as lurasidone is extensively metabolised (through oxidative N-dealkylation between the piperazine and cyclohexane rings) by CYP450, forming lurasidone metabolites 14326, 14283 (both active) and 20219, 20220 (inactive) [43].…”

Section: Implications and Future Directionsmentioning

confidence: 99%

“…of escitalopram responders and non-responders (C57BL/6 male mice model, n: 7/group, mean age: 4-6 weeks)45 . Furthermore, the gut microbiome has shown capacity to modulate hepatic cytochrome P450 (CYP450) characteristics as explored by Wang et al and Bai et al46,47 . In the context of lurasidone, it presents another avenue of pharmacokinetic modulation as lurasidone is extensively metabolised (thought oxidative N-dealkylation between the piperazine and cyclohexane rings) by CYP450, forming lurasidone metabolites 14326, 14283…”

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confidence: 99%

The Oral Bioavailability of Lurasidone is Impacted by Changes to the Gut Microbiome: Implications for Antipsychotic Therapy

Collins,

Kamath,

Meola

et al. 2024

Preprint

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This study investigates the impact of gut microbiome composition on the bioavailability and biodistribution of lurasidone hydrochloride, an atypical antipsychotic used in treating mental health conditions. The research aims to uncover the relationship between gut metabolome, specifically short-chain fatty acids (SCFAs), and lurasidone absorption through modulation of intestinal pH. Male Sprague-Dawley rats underwent a 14-day microbiome depletion using antibiotics or prebiotics administered via drinking water, resulting in depleted, enriched, or normal (control) microbiomes. Following this treatment, lurasidone was orally administered to fasted rats, and blood samples were collected at specific intervals to correlate pharmacokinetic analysis with changes in microbiota and metabolome composition. Results revealed a significant 4.3-fold increase in lurasidone bioavailability following prebiotic administration, while antibiotic treatment decreased bioavailability. This effect is attributed to prebiotics increasing microbial diversity, which strongly correlates with SCFA production (R² = 0.93). The subsequent lowering of intestinal pH created a more suitable environment for lurasidone solubility and absorption. This novel study establishes a clear relationship between gut microbiome composition and lurasidone bioavailability, with prebiotic administration positively impacting both gut microbial diversity and drug absorption. Thus, these findings suggest that gut microbiome manipulation may present an innovative approach to improving therapeutic outcomes for antipsychotic medications, potentially addressing poor response rates in some patients. Furthermore, this research highlights the importance of considering gut microbiome composition, in particular the use of SCFAs as a biomarker to produce predictive models of drug pharmacokinetics, especially for pH-dependent soluble drugs. In the context of drug efficacy these gut microbiome-based predictive pharmacokinetic models will pave the path for personalised medicine approaches for mental health treatment.Graphical Abstract

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Gut flora alterations among aquatic firefly Aquatica leii inhabiting various dissolved oxygen in fresh water

Zhao,

Yang,

et al. 2023

iScience

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Regulation of CYP450 and drug transporter mediated by gut microbiota under high-altitude hypoxia

Cited by 6 publications

References 36 publications

HNF4α improves hepatocyte regeneration by upregulating PXR

HNF4α improves hepatocyte regeneration by upregulating PXR

The Oral Bioavailability of Lurasidone is Impacted by Changes to the Gut Microbiome: Implications for Antipsychotic Therapy

Gut flora alterations among aquatic firefly Aquatica leii inhabiting various dissolved oxygen in fresh water

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