Host: The Japanese Society of Toxicology
[Purpose] Platelet activation is known to involve in liver injury. In addition to classical activation leading to blood coagulation, activation by mitochondrial permeability transition (MPT) is drawing attention from pathophysiological point of view. In the present study, we examined if MPT-mediated platelet activation is involved in acetaminophen (APAP)-induced liver injury in mice.
[Methods] Drug-induced MPT in isolated platelet was evaluated using flowcytometry. C57B6/J mice (8 week-old) were fasted overnight and treated with 300 mg/kg APAP. Platelet accumulation was assessed in frozen liver section. Ca2+-induced MPT was evaluated by decrease of the absorbance at 540 nm using isolated liver mitochondria.
[Result & Discussion] Isolated platelets were activated by well-known MPT-inducers, such as amiodarone and troglitazone in the presence of thrombin. These activations were not observed in platelets from cyclophilin D (regulator of MPT pore opening) knockout mice, indicating that platelet could be activated by drug compounds via MPT. Increased susceptibility to Ca2+-induced MPT and platelet accumulation in the liver was observed 2 hr after APAP administration prior to ALT increase. The enhancement of MPT sensitivity was suppressed by pre-administration of either heparin (anticoagulant) or cyclosporin A (MPT inhibitor), implying that APAP administration first induced blood coagulation and MPT in any cells, resulting in increased hepatic MPT sensitivity. Although not strictly proven, MPT-mediated platelet activation might occur in APAP-induced liver injury model mice.
