Effects of p-Cresol on Oxidative Stress, Glutathione Depletion, and Necrosis in HepaRG Cells: Comparisons to Other Uremic Toxins and the Role of p-Cresol Glucuronide Formation

Zhu, Sang; Rong, Yan; Kiang, Tony K. L.

doi:10.3390/pharmaceutics13060857

Cited by 15 publications

(9 citation statements)

References 47 publications

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“…These toxins are protein-bound and are, therefore, hard to remove, which leads to their abnormal blood circulating concentrations, exert harmful biological activity on other organs ( 27 ). Although PCS was found to induce oxidative stress, glutathione depletion, and cellular necrosis in a human liver cell line, more evidence is needed to clarify the effects of gut-derived PBUTs on hepatocytes ( 11 ). In this study, we determined the effects of 0–5 mM HA, IS, PCS, and KCL on HepG2 cell viability ( Figure 1A ).…”

Section: Resultsmentioning

confidence: 99%

“…Several PBUTs originate from the gut and are metabolized in the liver ( 6 ), which have been confirmed to impair insulin resistance, kidney fibrosis, granulocyte function, and cardiovascular health ( 9 , 35 ). Several recent studies evidenced that PBUTs induced oxidative stress, glutathione depletion, cellular necrosis, and bile acid transport disorders in the liver ( 6 , 8 , 11 , 12 ). However, more evidence is needed to clarify the impact of PBUTs on the liver.…”

Section: Discussionmentioning

confidence: 99%

“…Notably, patients with primary renal disease often have coexisting liver disease, which presents diagnostic and treatment challenges ( 10 ). Zhu et al found that PCS induced oxidative stress, glutathione depletion, and cellular necrosis in human hepatocytes ( 11 ). IS and PCS could affect hepatic bile acid transport and mitochondrial functions ( 6 , 8 ).…”

Section: Introductionmentioning

confidence: 99%

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Short-Chain Fatty Acids Alleviate Hepatocyte Apoptosis Induced by Gut-Derived Protein-Bound Uremic Toxins

Deng

et al. 2021

Front. Nutr.

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Chronic kidney disease (CKD) is characterized with the influx of uremic toxins, which impairs the gut microbiome by decreasing beneficial bacteria that produce short-chain fatty acids (SCFAs) and increasing harmful bacteria that produce gut-derived protein-bound uremic toxins (PBUTs). This study aimed to assess the proapoptotic effects of three major gut-derived PBUTs in hepatocytes, and the effects of SCFAs on apoptosis phenotype in vitro. HepG2 (human liver carcinoma cells) and THLE-2 (immortalized human normal liver cells) cell line were incubated with 0, 2, 20, 200, 2000 μM p-cresol sulfate (PCS), indoxyl sulfate (IS), and hippuric acid (HA), respectively, for 24 h. Flow cytometry analysis indicated that three uremic toxins induced varying degrees of apoptosis in hepatocytes and HA represented the highest efficacy. These phenotypes were further confirmed by western blot of apoptosis protein expression [Caspase-3, Caspase-9, B-cell lymphoma 2 (Bcl-2), and Bcl-2-associated X protein (Bax)]. Human normal hepatocytes (THLE-2) are more sensitive to PBUTs-induced apoptosis compared with human hepatoma cells (HepG2). Mechanistically, extracellular HA could enter hepatocytes, increase reactive oxygen species (ROS) generation, and decrease mitochondrial membrane potential dose-dependently in THLE-2 cells. Notably, coculture with SCFAs (acetate, propionate, butyrate) for 24 h significantly improved HA-induced apoptosis in THLE-2 cells, and propionate (500 μM) represented the highest efficacy. Propionate reduction of apoptosis was associated with improving mitochondria dysfunction and oxidative stress in a manner involving reducing Caspase-3 expression, ROS production, and increasing the Bcl-2/Bax level. As such, our studies validated PBUTs accumulation might be an important cause of liver dysfunction in patients with CKD, and supplementation of SCFAs might be a viable way to protect the liver for patients with CKD.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Short-Chain Fatty Acids Alleviate Hepatocyte Apoptosis Induced by Gut-Derived Protein-Bound Uremic Toxins

Deng

et al. 2021

Front. Nutr.

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“…Despite accounting for only 2% of total p-cresol in the blood, p-cresol accumulates in various organs of HD patients (12). So, the effects of p-cresol are attributed not only to the products of its metabolism but also to p-cresol itself (39). Because the liver is the primary site for its metabolism (40), free p-cresol is the major component of total p-cresol, followed by its conjugates (12).…”

Section: Discussionmentioning

confidence: 99%

Effects of p-cresol, a uremic toxin, on cancer cells

Chen¹,

Fei²,

Cao³

et al. 2023

Transl Cancer Res

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Background: Though p-cresol exists at a low concentration in the blood, it accumulates in various organs of uremic patients. Previous research has shown that the p-cresol promoted bladder cancer cell invasion and migration. This study aims to see if p-cresol had similar effects on kidney cancer cells and liver cancer cells. Methods: For 48 hours, 786-O human renal cancer cells and HepG2 human liver cancer cells were treated with p-cresol at concentrations of 0, 10, 20, 40, and 70 μM. The effects of p-cresol on cell viability, apoptosis, migration, and invasion were then analyzed using the CCK-8, TUNEL, and Transwell migration/invasion assays, respectively. Results: P-cresol at 0 to 70 μM for 48 hours had no significant toxic effects on 786-O cells or HepG2 cells. We chose 40 μM p-cresol for 48 hours for the following experiment. The viability and proliferation of 786-O cells and HepG2 cells were unaffected after 48 hours of treatment, with 40 μM p-cresol. However, 40 μM p-cresol for 48 hours promoted HepG2 cell migration and invasion but did not have the same effect on the 786-O cell line.Conclusions: P-cresol may be responsible for HepG2 cells' malignant biological behavior. Because the liver is the primary site of p-cresol metabolism, it is important to study the responses of cancer cells in the liver to p-cresol.

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“…Promoting the removal of 4EP from the body by driving its metabolism to increase excretion of soluble forms is theoretically possible. For example, the glucuronidated form of 4MP has reduced immune activating and inflammatory effects, when compared to 4MP and 4MPS ( Meert et al, 2012 ; Zhu, Rong, and Kiang, 2021 ) . Notably, only 8%–24% of 4-methylphenol glucuronide is protein bound in the blood, hence 4-methylphenol glucuronide is filtered out of the blood more easily, with 79% being removed by hemofiltration in chronic kidney disease patients ( Meert et al, 2012 ; Poesen et al, 2016 ).…”

Section: Future Directionsmentioning

confidence: 99%

4-Ethylphenol—fluxes, metabolism and excretion of a gut microbiome derived neuromodulator implicated in autism

Day,

O’Sullivan,

Pook

2023

Front. Mol. Biosci.

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Gut-microbiome-derived metabolites, such as 4-Ethylphenol [4EP], have been shown to modulate neurological health and function. Although the source of such metabolites is becoming better understood, knowledge gaps remain as to the mechanisms by which they enter host circulation, how they are transported in the body, how they are metabolised and excreted, and the way they exert their effects. High blood concentrations of host-modified 4EP, 4-ethylphenol sulfate [4EPS], are associated with an anxiety phenotype in autistic individuals. We have reviewed the existing literature and discuss mechanisms that are proposed to contribute influx from the gut microbiome, metabolism, and excretion of 4EP. We note that increased intestinal permeability is common in autistic individuals, potentially explaining increased flux of 4EP and/or 4EPS across the gut epithelium and the Blood Brain Barrier [BBB]. Similarly, kidney dysfunction, another complication observed in autistic individuals, impacts clearance of 4EP and its derivatives from circulation. Evidence indicates that accumulation of 4EPS in the brain of mice affects connectivity between subregions, particularly those linked to anxiety. However, we found no data on the presence or quantity of 4EP and/or 4EPS in human brains, irrespective of neurological status, likely due to challenges sampling this organ. We argue that the penetrative ability of 4EP is dependent on its form at the BBB and its physicochemical similarity to endogenous metabolites with dedicated active transport mechanisms across the BBB. We conclude that future research should focus on physical (e.g., ingestion of sorbents) or metabolic mechanisms (e.g., conversion to 4EP-glucuronide) that are capable of being used as interventions to reduce the flux of 4EP from the gut into the body, increase the efflux of 4EP and/or 4EPS from the brain, or increase excretion from the kidneys as a means of addressing the neurological impacts of 4EP.

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Effects of p-Cresol on Oxidative Stress, Glutathione Depletion, and Necrosis in HepaRG Cells: Comparisons to Other Uremic Toxins and the Role of p-Cresol Glucuronide Formation

Cited by 15 publications

References 47 publications

Short-Chain Fatty Acids Alleviate Hepatocyte Apoptosis Induced by Gut-Derived Protein-Bound Uremic Toxins

Short-Chain Fatty Acids Alleviate Hepatocyte Apoptosis Induced by Gut-Derived Protein-Bound Uremic Toxins

Effects of p-cresol, a uremic toxin, on cancer cells

4-Ethylphenol—fluxes, metabolism and excretion of a gut microbiome derived neuromodulator implicated in autism

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