Protective Effect of Melatonin on Rat Liver Injury Induced by Bile Duct Ligation_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

ZHANG Xiaoming ^1,2 , MA Pingan ² , CHEN Jiaxian ² , KOU Zhimin ¹ ,  ZHANG Youcheng ¹

1.Department of General Surgery， The Second Affiliated Hospital of Lanzhou University， Lanzhou 730030， China;;
2.Department of General Surgery， People’s Hospital of Qingyang City， Qingyang 745000， Gansu Province， China;

Corresponding author：

ZHANG Youcheng, Email: zhangychmd@yahoo.com.cn

Keywords：

Melatonin; Obstructive jaundice; Liver injury; Antioxidant; Apoptosis; TUNEL method

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Objective 　To investigate the protective effect of melatonin on rat liver injury induced by bile duct ligation.
Methods 　Sixty-four rats were randomly divided into four groups：control group （CN group， n=16）， sham
operation group （SO group， n=16）， bile duct ligation group （BDL group， n=16）， and bile duct ligation with melatonin injection （BDL＋MT group， n=16）. The model of obstructive jaundice was done by ligation of the common bile duct. Melatonin was injected daily （0.5 mg/kg） via peritoneal cavity from 1 d before the operation to 7 d following oper-
ation. On day 4 and 8 after the ligation， the plasma levels of total bilirubin （TBIL）， alanine aminotransferase （ALT）， aspartate aminotransferase （AST）， gamma glutamyl transferase （GGT）， and alkaline phosphatase （AKP） were measured by routine methods. Malonaldehyde （MDA）， superoxide dismutase （SOD）， glutathione （GSH）， catalase （CAT）， and glutathione peroxidase （GSH-Px） in the liver tissue were determined by spectrophtometry， too. Hepatocytes apoptosis was analyzed by terminal deoxynucleotidyl transferase-mediated deoxynuridine triphosphate nick-end labeling （TUNEL） assay.
Results 　Compared with the CN group and SO group， the levels of TBIL， ALT， AST， GGT， and AKP in the plasma， the content of MDA in the liver tissue， and the apoptosis index （AI） in the hepatocyte markedly increased （P＜0.05， P＜0.01）， the content of GSH and the activities of SOD， CAT， and GSH-Px in the liver tissue markedly decreased（P＜0.01） in the BDL group. Compared with the BDL group， the levels of TBIL， ALT， AST， GGT， and AKP in the plasma， the content of MDA in the liver tissue， and the AI in the hepatocyte markedly decreased （P＜0.01）， the content of GSH and the activities of SOD， CAT， and GSH-Px in the liver tissue markedly increased （P＜0.01） in the BDL＋MT group. In the BDL group， the level of MDA in the liver tissue and the levels of TBIL， ALT， AST， GGT， and AKP were positively correlated （P＜0.01）， the content of GSH and the activities of SOD， CAT， and GSH-Px in the liver tissue and TBIL， ALT， AST， GGT， and AKP were negatively correlated （P＜0.01）. The level of MDA in the liver tissue and AI in the hepatocyte was positively correlated （P＜0.01）. The content of GSH and the activities of SOD， CAT， and GSH-Px in the liver tissue and AI were negatively correlated （P＜0.01）.
Conclusions 　The participation of free radical of oxygen in the pathogenesis and severity of cholestasis produced by the acute obstruction of the extra-hepatic biliary duct is likely. The result of the present study indicates that melatonin exerts a protective effect on cholestatic liver injury in rats with BDL. The mechanism of melatonin’s protection on hepatocyte may be through its antioxidant action and by inhibiting hepatocyte apoptosis.

Citation： ZHANG Xiaoming,MA Pingan,CHEN Jiaxian,KOU Zhimin,ZHANG Youcheng. Protective Effect of Melatonin on Rat Liver Injury Induced by Bile Duct Ligation. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2013, 20(8): 878-883. doi: Copy

1.	Gonzalez-Correa JA， De La Cruz JP， Martin-Aurioles E， et al. Effects of S-adenosyl-L-methionine on hepatic and renal oxidativestress in an experimental model of acute biliary obstruction in rats[J]. Hepatology， 1997， 26(1)：121-127.
2.	张永刚，迟彦邦，杨彤翰，等. 胆道梗阻后肝脏自由基损伤及粉防己碱保护作用的实验研究[J]. 中华实验外科杂志， 1999， 16(5)：406-407.
3.	Granato A， Gores G， Vilei MT， et al. Bilirubin inhibits bile acid induced apoptosis in rat hepatocytes[J]. Gut， 2003， 52(12)：1774-1778.
4.	李明正. 褪黑素的抗自由基氧化损伤和防护作用[J]. 国外医学：卫生学分册， 2000， 27(1)：26-29.
5.	Shaker ME， Houssen ME， Abo-Hashem EM， et al. Comparison of vitamin E， L-carnitine and melatonin in ameliorating Carbon tetrachloride and diabetes induced hepatic oxidative stress[J]. J Physiol Biochem， 2009， 65(3)：225-233.
6.	Ohta Y， Kongo M， Kishikawa T. Melatonin exerts a therapeutic effect on cholestatic liver injury in rats with bile duct ligation[J]. J Pineal Res， 2003， 34(2)：119-126.
7.	Cruz A， Padillo FJ， Túnez I， et al. Melatonin protects against renal oxidative stress after obstructive jaundice in rats[J]. Eur J Pharmacol， 2001， 425(2)：135-139.
8.	Aktas C， Kanter M， Erboga M， et al. Melatonin attenuates oxid-ative stress， liver damage and hepatocyte apoptosis after bile-duct ligation in rats[J]. Toxicol Ind Health， 2012 Oct 24. [Epub ahead of print].
9.	张小明，寇治民，康二虎，等. 褪黑素对大鼠梗阻性黄疸肾损害的保护作用[J]. 中国普外基础与临床杂志， 2005， 12(1)：55-58.
10.	Montilla P， Cruz A， Padillo FJ， et al. Melatonin versus vitamin E as protective treatment against oxidative stress after extra-hepatic bile duct ligation in rats[J]. J Pineal Res， 2001， 31(2)：138-144.
11.	Inan M， Sayek I， Tel BC， et al. Role of endotoxin and nitric oxidein the pathogenesis of renal failure in obstructive jaundice[J]. BrJ Surg， 1997， 84(7)：943-947.
12.	Hu S， Yin S， Jiang X， et al. Melatonin protects against alcoholic liver injury by attenuating oxidative stress， inflammatory response， and apoptosis[J]. Eur J Pharmacol， 2009， 616(1-3)：287-292.
13.	Brown KM， Brems JJ， Moazzam FN， et al. The nitric oxide donormolsidomine improves survival and reduces hepatocyte apoptosis in cholestasis and endotoxemia[J]. J Am Coll Surg， 2003， 197(2)：261-269.
14.	Andrabi SA， Sayeed I， Siemen D， et al. Direct inhibition of the mitochondrial permeability transition pore：a possible mechanism responsible for anti-apoptotic effects of melatonin[J]. FASEB J， 2004， 18(7)：869-871.
15.	Jones BA， Rao YP， Stravitz RT， et al. Bile salt-induced apoptosisof hepatocytes involves activation of protein kinase C[J]. Am J Physiol， 1997， 272(5 Pt 1)：G1109-G1115.
16.	Kayanoki Y， Fujii J， Islam KN， et al. The protective role of glutathione peroxidase in apoptosis induced by reactive oxygen species[J]. J Biochem， 1996， 119(4)：817-822.
17.	洪汝涛，陈世林，阮海玲，等. 褪黑素对大鼠急性酒精性肝损伤的作用[J]. 中国药理学通报， 2011， 27(11)：1596-1599.
18.	陈风，汤琳，汪健，等. 胰胆管合流异常胆道损伤抗氧化治疗的实验研究[J]. 中国普外基础与临床杂志， 2012， 19(10)：1069-1073.
19.	Kang JW， Lee SM. Melatonin inhibits type 1 interferon signaling of toll-like receptor 4 via heme oxygenase-1 induction in hepatic ischemia/reperfusion[J]. J Pineal Res， 2012， 53(1)：67-76.
20.	Hsu JT， Kuo CJ， Chen TH， et al. Melatonin prevents hemorrhagic shock-induced liver injury in rats through an Akt-dependent HO-1 pathway[J]. J Pineal Res， 2012， 53(4)：410-416.
21.	Cheshchevik VT， Lapshina EA， Dremza IK， et al. Rat livermitochondrial damage under acute or chronic Carbon tetrachloride-induced intoxication：protection by melatonin and cranberry flavo-noids[J]. Toxicol Appl Pharmacol， 2012， 261(3)：271-279.
22.	Wang H， Xu DX， Lv JW， et al. Melatonin attenuates lipopolysaccharide (LPS)-induced apoptotic liver damage in D-galactosamine-sensitized mice[J]. Toxicology， 2007， 237(1-3)：49-57.
23.	El-Missiry MA， Fayed TA， El-Sawy MR， et al. Ameliorative effect of melatonin against gamma-irradiation-induced oxidativestress and tissue injury[J]. Ecotoxicol Environ Saf， 2007， 66(2)：.
24.	Jahovic N， Cevik H， Sehirli AO， et al. Melatonin prevents methotrexate-induced hepatorenal oxidative injury in rats[J]. J Pineal Res， 2003， 34(4)：282-287.
25.	Korkmaz GG， Uzun H， Cakatay U， et al. Melatonin ameliorates oxidative damage in hyperglycemia-induced liver injury[J]. Clin Invest Med， 2012， 35(6)：E370-E377.
26.	Reiter RJ. Melatonin：that ubiquitously acting pineal hormone[J]. Physiology， 1991， 6(5)：223-227.
27.	López PM， Fiñana IT， De Agueda MC， et al. Protective effect of melatonin against oxidative stress induced by ligature of extra-hepatic biliary duct in rats：comparison with the effect of S-adenosyl-L-methionine[J]. J Pineal Res， 2000， 28(3)：143-149.
28.	-286.

1. Gonzalez-Correa JA， De La Cruz JP， Martin-Aurioles E， et al. Effects of S-adenosyl-L-methionine on hepatic and renal oxidativestress in an experimental model of acute biliary obstruction in rats[J]. Hepatology， 1997， 26(1)：121-127.
2. 张永刚，迟彦邦，杨彤翰，等. 胆道梗阻后肝脏自由基损伤及粉防己碱保护作用的实验研究[J]. 中华实验外科杂志， 1999， 16(5)：406-407.
3. Granato A， Gores G， Vilei MT， et al. Bilirubin inhibits bile acid induced apoptosis in rat hepatocytes[J]. Gut， 2003， 52(12)：1774-1778.
4. 李明正. 褪黑素的抗自由基氧化损伤和防护作用[J]. 国外医学：卫生学分册， 2000， 27(1)：26-29.
5. Shaker ME， Houssen ME， Abo-Hashem EM， et al. Comparison of vitamin E， L-carnitine and melatonin in ameliorating Carbon tetrachloride and diabetes induced hepatic oxidative stress[J]. J Physiol Biochem， 2009， 65(3)：225-233.
6. Ohta Y， Kongo M， Kishikawa T. Melatonin exerts a therapeutic effect on cholestatic liver injury in rats with bile duct ligation[J]. J Pineal Res， 2003， 34(2)：119-126.
7. Cruz A， Padillo FJ， Túnez I， et al. Melatonin protects against renal oxidative stress after obstructive jaundice in rats[J]. Eur J Pharmacol， 2001， 425(2)：135-139.
8. Aktas C， Kanter M， Erboga M， et al. Melatonin attenuates oxid-ative stress， liver damage and hepatocyte apoptosis after bile-duct ligation in rats[J]. Toxicol Ind Health， 2012 Oct 24. [Epub ahead of print].
9. 张小明，寇治民，康二虎，等. 褪黑素对大鼠梗阻性黄疸肾损害的保护作用[J]. 中国普外基础与临床杂志， 2005， 12(1)：55-58.
10. Montilla P， Cruz A， Padillo FJ， et al. Melatonin versus vitamin E as protective treatment against oxidative stress after extra-hepatic bile duct ligation in rats[J]. J Pineal Res， 2001， 31(2)：138-144.
11. Inan M， Sayek I， Tel BC， et al. Role of endotoxin and nitric oxidein the pathogenesis of renal failure in obstructive jaundice[J]. BrJ Surg， 1997， 84(7)：943-947.
12. Hu S， Yin S， Jiang X， et al. Melatonin protects against alcoholic liver injury by attenuating oxidative stress， inflammatory response， and apoptosis[J]. Eur J Pharmacol， 2009， 616(1-3)：287-292.
13. Brown KM， Brems JJ， Moazzam FN， et al. The nitric oxide donormolsidomine improves survival and reduces hepatocyte apoptosis in cholestasis and endotoxemia[J]. J Am Coll Surg， 2003， 197(2)：261-269.
14. Andrabi SA， Sayeed I， Siemen D， et al. Direct inhibition of the mitochondrial permeability transition pore：a possible mechanism responsible for anti-apoptotic effects of melatonin[J]. FASEB J， 2004， 18(7)：869-871.
15. Jones BA， Rao YP， Stravitz RT， et al. Bile salt-induced apoptosisof hepatocytes involves activation of protein kinase C[J]. Am J Physiol， 1997， 272(5 Pt 1)：G1109-G1115.
16. Kayanoki Y， Fujii J， Islam KN， et al. The protective role of glutathione peroxidase in apoptosis induced by reactive oxygen species[J]. J Biochem， 1996， 119(4)：817-822.
17. 洪汝涛，陈世林，阮海玲，等. 褪黑素对大鼠急性酒精性肝损伤的作用[J]. 中国药理学通报， 2011， 27(11)：1596-1599.
18. 陈风，汤琳，汪健，等. 胰胆管合流异常胆道损伤抗氧化治疗的实验研究[J]. 中国普外基础与临床杂志， 2012， 19(10)：1069-1073.
19. Kang JW， Lee SM. Melatonin inhibits type 1 interferon signaling of toll-like receptor 4 via heme oxygenase-1 induction in hepatic ischemia/reperfusion[J]. J Pineal Res， 2012， 53(1)：67-76.
20. Hsu JT， Kuo CJ， Chen TH， et al. Melatonin prevents hemorrhagic shock-induced liver injury in rats through an Akt-dependent HO-1 pathway[J]. J Pineal Res， 2012， 53(4)：410-416.
21. Cheshchevik VT， Lapshina EA， Dremza IK， et al. Rat livermitochondrial damage under acute or chronic Carbon tetrachloride-induced intoxication：protection by melatonin and cranberry flavo-noids[J]. Toxicol Appl Pharmacol， 2012， 261(3)：271-279.
22. Wang H， Xu DX， Lv JW， et al. Melatonin attenuates lipopolysaccharide (LPS)-induced apoptotic liver damage in D-galactosamine-sensitized mice[J]. Toxicology， 2007， 237(1-3)：49-57.
23. El-Missiry MA， Fayed TA， El-Sawy MR， et al. Ameliorative effect of melatonin against gamma-irradiation-induced oxidativestress and tissue injury[J]. Ecotoxicol Environ Saf， 2007， 66(2)：.
24. Jahovic N， Cevik H， Sehirli AO， et al. Melatonin prevents methotrexate-induced hepatorenal oxidative injury in rats[J]. J Pineal Res， 2003， 34(4)：282-287.
25. Korkmaz GG， Uzun H， Cakatay U， et al. Melatonin ameliorates oxidative damage in hyperglycemia-induced liver injury[J]. Clin Invest Med， 2012， 35(6)：E370-E377.
26. Reiter RJ. Melatonin：that ubiquitously acting pineal hormone[J]. Physiology， 1991， 6(5)：223-227.
27. López PM， Fiñana IT， De Agueda MC， et al. Protective effect of melatonin against oxidative stress induced by ligature of extra-hepatic biliary duct in rats：comparison with the effect of S-adenosyl-L-methionine[J]. J Pineal Res， 2000， 28(3)：143-149.
28. -286.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Protective Effect of Melatonin on Rat Liver Injury Induced by Bile Duct Ligation

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