A phosphodiesterase III inhibitor protects rat liver from sinusoidal obstruction syndrome through heme oxygenase-1 induction.

Abstract

The aim of study was to investigate pharmacological treatment for sinusoidal obstruction syndrome (SOS). SOS is associated with oxaliplatin-based chemotherapy in patients with hepatic colorectal metastases. Patients with SOS have increased postoperative morbidity after major hepatectomy, but a method for effective prevention of SOS has not been established. Male Sprague-Dawley rats were treated with cobalt protoporphyrin IX (CoPP) or olprinone (OLP), a phosphodiesterase III inhibitor, and hepatic HO-1 expression and HO enzymatic activity were determined. Monocrotaline (MCT) was given to rats to induce SOS, and blockage of SOS by CoPP or OLP-induced hepatic HO-1 was examined in these rats. Zinc protoporphyrin IX (ZnPP), a competitive HO inhibitor, was given to MCT-treated rats together with OLP to clarify the mechanism of protection against SOS. We also examined if OLP preserved remnant liver function after 70% hepatectomy in MCT-treated rats. OLP up-regulated hepatic HO-1 protein expression and HO enzymatic activity, and activated Akt protein. Administration of ZnPP to OLP-treated rats resulted in inhibition of HO activity and inactivation of Akt. Induction of HO-1 by pretreatment with CoPP led to amelioration of SOS in histologic findings and blockage of elevation of serum liver enzymes. Pretreatment with OLP gave a similar result and preserved remnant liver function, as indicated by improved survival after hepatectomy. ZnPP completely abolished the protective effects of OLP. Protection of the liver from drug-induced injury by prior up-regulation of HO-1 using OLP may have potential as a therapeutic strategy for prevention of SOS.