Proteomic study of pyrrolizidine alkaloid-induced hepatic sinusoidal obstruction syndrome in rats.
Pyrrolizidine alkaloids (PAs) are a group of phytotoxins that can induce human liver injury, particularly hepatic sinusoidal obstruction syndrome (HSOS). To date, the molecular targets of PA-induced HSOS are largely unknown. In this study, retrorsine (RTS), a known hepatotoxic PA, was used as a representative PA for proteomic studies. Toxicological assessment demonstrated that 35 mg/kg RTS (designated as RTS-L) caused early lesions of HSOS at 24 h after dosing. A proteomic approach revealed 17 up-regulated and 31 down-regulated proteins in RTS-L-treated rats. Subsequently, bioinformatic analysis suggested that two proteins, carbamoyl-phosphate synthase (CPS1) (p < 0.05) and ATP synthase subunit beta (ATP5B) (p < 0.01) were associated with RTS-L intoxication. Using immunohistochemical staining, we further verified the down-regulation of CPS1 and ATP5B in RTS-L-treated rats. These findings indicated that CPS1 and ATP5B were altered in the RTS-induced early lesions of HSOS in rats, and therefore, these two proteins and their involved pathways might play important roles in the initiation of HSOS. To the best of our knowledge, our study using a proteomic approach combined with conventional toxicological assessment is the first systems toxicology study on PA-induced HSOS. The results of this study provide novel findings on protein profiles in response to PA exposure, which can serve as a starting point to further investigate potential protein targets and their interactions with PAs to induce HSOS.
School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong , Hong Kong, China.
Yan-Hong
YH
Li
Centre of Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University , Hong Kong, China.|Institute of Integrated Bioinfomedicine & Translational Science, Hong Kong Baptist University Shenzhen Research Institute and Continuing Education , Shenzhen, China.
William Chi-Shing
WC
Tai
School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong , Hong Kong, China.
Jun-Yi
JY
Xue
Centre of Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University , Hong Kong, China.
Wing-Yan
WY
Wong
Centre of Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University , Hong Kong, China.|Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences , Beijing, China.
Cheng
C
Lu
School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong , Hong Kong, China.
Jian-Qing
JQ
Ruan
School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong , Hong Kong, China.
Na
N
Li
School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong , Hong Kong, China.
Tai-Fung
TF
Wan
School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong , Hong Kong, China.
Wood-Yee
WY
Chan
State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology , Macau, China.
Wen-Luan Wendy
WL
Hsiao
School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong , Hong Kong, China.
Ge
G
Lin
D000818:Animals; D016000:Cluster Analysis; D006504:Hepatic Veno-Occlusive Disease / Q000139:chemically induced*; D008297:Male; D040901:Proteomics; D011763:Pyrrolizidine Alkaloids / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley
D011763:Pyrrolizidine Alkaloids