Antiplatelet effect by p-cresol, a uremic and environmental toxicant, is related to inhibition of reactive oxygen species, ERK/p38 signaling and thromboxane A(2) production

作者：Chang Mei Chi; Wang Tong Mei; Yeung Sin Yuet; Jeng Po Yuan; Liao Chang Hui; Lin Tzu Yung; Lin Chiu Chun; Lin Bor Ru; Jeng Jiiang Huei^*

来源：Atherosclerosis, 2011, 219(2): 559-565.

DOI：10.1016/j.atherosclerosis.2011.09.031

• P-cresol
• Uremia
• Environmental toxicant
• Platelet aggregation
• Reactive oxygen species
• Thromboxane A(2)

P-cresol is a well-known uremic toxin and environmental toxicant that may affect platelet functions. In this study, p-cresol (1-5 mu M) inhibited the arachidonic acid (AA)-induced platelet aggregation, with 47% and 82% of inhibition at concentrations of 2 and 5 mu M, respectively. Under similar experimental condition, p-cresol showed little effect on the U46619-induced platelet aggregation. p-cresol (<500 mu M) 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 mu M) 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 mu M and aggregation of human PRP (IC50 = 13.6 mu M). 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.

• 出版日期2011-12
• 单位长春大学