p-Cresol affects reactive oxygen species generation, cell cycle arrest, cytotoxicity and inflammation/atherosclerosis-related modulators production in endothelial cells and mononuclear cells.

Abstract

AIMS:

Cresols are present in antiseptics, coal tar, some resins, pesticides, and industrial solvents. Cresol intoxication leads to hepatic injury due to coagulopathy as well as disturbance of hepatic circulation in fatal cases. Patients with uremia suffer from cardiovascular complications, such as atherosclerosis, thrombosis, hemolysis, and bleeding, which may be partly due to p-cresol toxicity and its effects on vascular endothelial and mononuclear cells. Given the role of reactive oxygen species (ROS) and inflammation in vascular thrombosis, the objective of this study was to evaluate the effect of p-cresol on endothelial and mononuclear cells.

METHODS:

EA.hy926 (EAHY) endothelial cells and U937 cells were exposed to different concentrations of p-cresol. Cytotoxicity was evaluated by 3-(4,5-Dimethylthiazol-2-yl)-2,5 -diphenyltetrazolium bromide (MTT) assay and trypan blue dye exclusion technique, respectively. Cell cycle distribution was analyzed by propidium iodide flow cytometry. Endothelial cell migration was studied by wound closure assay. ROS level was measured by 2',7'-dichlorofluorescein diacetate (DCF) fluorescence flow cytometry. Prostaglandin F2α (PGF2α), plasminogen activator inhibitor-1 (PAI-1), soluble urokinase plasminogen activator receptor (suPAR), and uPA production were determined by Enzyme-linked immunosorbant assay (ELISA).

RESULTS:

Exposure to 100-500 µM p-cresol decreased EAHY cell number by 30-61%. P-cresol also decreased the viability of U937 mononuclear cells. The inhibition of EAHY and U937 cell growth by p-cresol was related to induction of S-phase cell cycle arrest. Closure of endothelial wounds was inhibited by p-cresol (>100 µM). P-cresol (>50 µM) also stimulated ROS production in U937 cells and EAHY cells but to a lesser extent. Moreover, p-cresol markedly stimulated PAI-1 and suPAR, but not PGF2α, and uPA production in EAHY cells.

CONCLUSIONS:

p-Cresol may contribute to atherosclerosis and thrombosis in patients with uremia and cresol intoxication possibly due to induction of ROS, endothelial/mononuclear cell damage and production of inflammation/atherosclerosis-related molecules.

• Authors: Mei-Chi Chang, Hsiao-Hua Chang, Chiu-Po Chan, Sin-Yuet Yeung, Hsiang-Chi Hsien, Bor-Ru Lin, Chien-Yang Yeh, Wan-Yu Tseng, Shui-Kuan Tseng, Jiiang-Huei Jeng
• Journal: PloS one (PLoS One) Vol. 9 Issue 12 Pg. e114446 ( 2014) ISSN: 1932-6203 [Electronic] United States
• PMID: 25517907 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cresols
• Plasminogen Activator Inhibitor 1
• Reactive Oxygen Species
• Receptors, Urokinase Plasminogen Activator
• 4-cresol
• Dinoprost
• Urokinase-Type Plasminogen Activator

Topics

• Apoptosis (drug effects)
• Atherosclerosis (metabolism)
• Cell Cycle Checkpoints (drug effects)
• Cell Proliferation (drug effects)
• Cresols (toxicity)
• Dinoprost (biosynthesis)
• Endothelial Cells (drug effects, metabolism, pathology)
• Humans
• Inflammation (metabolism)
• Leukocytes, Mononuclear (drug effects, metabolism, pathology)
• Plasminogen Activator Inhibitor 1 (biosynthesis)
• Reactive Oxygen Species (metabolism)
• Receptors, Urokinase Plasminogen Activator (biosynthesis, chemistry)
• Solubility
• U937 Cells
• Urokinase-Type Plasminogen Activator (biosynthesis)