Therapeutic effects and possible mechanisms of a snake venom preparation in the fibrotic rat liver.
The effects of a Chinese snake venom preparation from Agkistrodon halys pallas, used for treatment of hepatic fibrosis/cirrhosis in China, was investigated in an in vivo rat model and using in situ hepatic perfusion. Four groups were used in the experiments: (i) healthy, (ii) healthy/venom-treated, (iii) carbon tetrachloride (CCl4)-treated, and (iv) CCl4/venom-treated. Treatment effects were assessed by determining hepatic histopathology, biochemistry and fibrosis index parameters, bile production, biliary taurocholate recovery, hepatic mRNA expression of four bile salt transporters (Ntcp, Bsep, Oatp-1, and Oatp-3), comparison of hepatic microcirculation, fibrinolytic activity, and antithrombotic effects. Liver histopathology, biochemistry, and fibrosis index showed a dramatic improvement in venom-treated animals. There were significant differences in bile production between healthy/venom-treated and all other experimental groups and between CCl4/venom-treated and CCl4-treated animals, but no significant differences were found between CCl4/venom-treated and healthy animals. Biliary taurocholate recovery was significantly increased in healthy/venom-treated and CCl4/venom-treated animals. The expression of mRNA levels of the four bile salt transporters showed an increase after venom treatment. The hepatic microcirculation studies showed normalized sinusoidal beds in CCl4/venom-treated animals compared to healthy animals, whereas CCl4-treated animals showed abnormal profiles to the healthy and the CCl4/AHPV-treated animals. The fibrinogen and plasma thromboxane B2 levels of healthy rats decreased with increasing dose after venom treatment. It was concluded that snake venom treatment may be therapeutic in treatment of hepatic fibrosis/cirrhosis by possibly a combination of increased bile flow and improved hepatic microcirculation, changes in bile salt transporter expression, and fibrinolytic and antithrombotic effects of the snake venom preparation.
Chang
Ping
P
Department of Medicine, University of Queensland, Princess Alexandra Hospital, Woolloongabba, Qld 4102, Australia.
Hung
Daniel Y
DY
Siebert
Gerhard A
GA
Bridle
Kim
K
Roberts
Michael S
MS
D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000818:Animals; D001646:Bile / Q000378:metabolism; D002251:Carbon Tetrachloride; D004305:Dose-Response Relationship, Drug; D005340:Fibrinogen / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008102:Liver Circulation / Q000187:drug effects; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics; D008833:Microcirculation / Q000187:drug effects; D029363:Organic Anion Transporters, Sodium-Dependent; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012910:Snake Venoms / Q000008:administration & dosage / Q000494:pharmacology*; D027981:Symporters; D013656:Taurocholic Acid / Q000378:metabolism; D013929:Thromboxane B2 / Q000097:blood
D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; C490548:Abcb11 protein, rat; D026901:Membrane Transport Proteins; D029363:Organic Anion Transporters, Sodium-Dependent; D029362:Organic Anion Transporters, Sodium-Independent; D012333:RNA, Messenger; C421102:Slco1a1 protein, rat; C421143:Slco1a5 protein, rat; D012910:Snake Venoms; D027981:Symporters; C071908:sodium-bile acid cotransporter; D013929:Thromboxane B2; D013656:Taurocholic Acid; D005340:Fibrinogen; D002251:Carbon Tetrachloride