A phosphodiesterase III inhibitor protects rat liver from sinusoidal obstruction syndrome through heme oxygenase-1 induction.
OBJECTIVE
The aim of study was to investigate pharmacological treatment for sinusoidal obstruction syndrome (SOS).


BACKGROUND
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Narita
Masato
M
Department of Surgery, Graduate School of Medicine, Kyoto University, Syogoin, Kyoto, Japan.
Hatano
Etsuro
E
Ikai
Iwao
I
Miyagawa-Hayashino
Aya
A
Yanagida
Atsuko
A
Nagata
Hiromitsu
H
Asechi
Hiroyuki
H
Taura
Kojiro
K
Uemoto
Shinji
S
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000601:surgery*; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D006504:Hepatic Veno-Occlusive Disease / Q000139:chemically induced / Q000517:prevention & control*; D007093:Imidazoles / Q000008:administration & dosage*; D008099:Liver / Q000187:drug effects; D008113:Liver Neoplasms / Q000188:drug therapy / Q000556:secondary / Q000601:surgery*; D008297:Male; D020360:Neoadjuvant Therapy; D009944:Organoplatinum Compounds / Q000009:adverse effects; D000077150:Oxaliplatin; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage*; D011728:Pyridones / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation
D000970:Antineoplastic Agents; D007093:Imidazoles; D009944:Organoplatinum Compounds; D010726:Phosphodiesterase Inhibitors; D011728:Pyridones; D000077150:Oxaliplatin; C059498:olprinone; D051547:Heme Oxygenase-1