title: Antiplatelet effect by p-cresol, a uremic and environmental toxicant, is related to inhibition of reactive oxygen species, ERK/p38 signaling and thromboxane A2 production.
abstract: P-cresol is a well-known uremic toxin and environmental toxicant that may affect platelet functions. In this study, p-cresol (1-5 μM) inhibited the arachidonic acid (AA)-induced platelet aggregation, with 47% and 82% of inhibition at concentrations of 2 and 5 μM, respectively. Under similar experimental condition, p-cresol showed little effect on the U46619-induced platelet aggregation. p-cresol (<500 μM) revealed no discernable cytotoxicity to platelets as analyzed by quantification of lactate dehydrogenase release. Antiplatelet effect of p-cresol was related to inhibition of thromboxane A(2) (TXA(2)) and prostaglandin D(2) (PGD(2)) formation. P-cresol (2-100 μM) partly inhibited the AA-induced reactive oxygen species (ROS) production as well as the extracellular signal-regulated kinase (ERK1/2) and p38 phosphorylation in platelets. P-cresol further inhibited the AA-induced aggregation of rabbit platelet-rich plasma (PRP) with an IC50 of 2 μM and aggregation of human PRP (IC50 = 13.6 μM). Intravenous administration of p-cresol (250-1000 nmole) into mice effectively suppressed the ex vivo platelet aggregation, whereas showed little effect on the value of RBC, hemoglobin (HGB), hematocrit, MCV, MCH, MCHC, platelets and lymphocyte counts. These results indicate that in acute p-cresol-poisoning and long-term exposure to cresol as in severe uremic patients, p-cresol may potentially inhibit blood clot formation and lead to hemorrhagic disorders via inhibition of platelet aggregation, ROS production, ERK/p38 activation and TXA(2) production.
authors: Biomedical Science Team, Chang Gung Institute of Technology, Taoyuan, Taiwan.
authors: Mei-Chi
authors: MC
authors: Chang
authors: Tong-Mei
authors: TM
authors: Wang
authors: Sin-Yuet
authors: SY
authors: Yeung
authors: Po-Yuan
authors: PY
authors: Jeng
authors: Chang-Hui
authors: CH
authors: Liao
authors: Tzu-Yung
authors: TY
authors: Lin
authors: Chiu-Chun
authors: CC
authors: Lin
authors: Bor-Ru
authors: BR
authors: Lin
authors: Jiiang-Huei
authors: JH
authors: Jeng
mesh_terms: D000818:Animals; D001772:Blood Cell Count; D001792:Blood Platelets / Q000187:drug effects* / Q000201:enzymology; D003408:Cresols / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004785:Environmental Pollutants / Q000633:toxicity*; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000097:blood*; D006801:Humans; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010766:Phosphorylation; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000633:toxicity*; D010979:Platelet Function Tests; D015230:Prostaglandin D2 / Q000097:blood; D011817:Rabbits; D017382:Reactive Oxygen Species / Q000097:blood*; D015398:Signal Transduction / Q000187:drug effects*; D013928:Thromboxane A2 / Q000097:blood*; D013997:Time Factors; D014511:Uremia / Q000097:blood / Q000139:chemically induced*; D048051:p38 Mitogen-Activated Protein Kinases / Q000097:blood*
chemical_list: D003408:Cresols; D004785:Environmental Pollutants; D010975:Platelet Aggregation Inhibitors; D017382:Reactive Oxygen Species; C032538:4-cresol; D013928:Thromboxane A2; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D015230:Prostaglandin D2