Saudi Journal of Gastroenterology
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Year : 1999  |  Volume : 5  |  Issue : 3  |  Page : 113-116
The beneficial effect of α-tocopherol on liver regeneration after partial hepatectomy on rats


Department of Surgery, King Khalid University Hospital, Riyadh, Saudi Arabia

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Date of Submission10-Feb-1999
Date of Acceptance27-Apr-1999
 

   Abstract 

Liver, a unique organ, is the only organ which has the ability to regenerate after partial hepatectomy. It can return to normal mass several weeks after 70% partial hepatectomy. The exact mechanism responsible for regeneration is yet to be known. This needs further investigation. The aim of this study is to examine the role of oxygen free radicals (OFRs) such as superoxide (0 - 2 ), hydroxyl radicals (H202 or OH - ) in liver regeneration after partial hepatectomy (<70%). To evaluate the effect of antioxidant on liver regeneration, rats were pre-treated intramuscularly with α-tocopherol (vitamin E) daily for 3 weeks, and continued for 3 weeks post partial hepatectomy (<70%) liver weight, rat body weight were determined in both control (untreated) and treated groups. The present results showed significant increase in liver weight in vitamin E treated group compared to control. The results of this paper might be useful in throwing some light on the role of oxygen free radical scavengers and antioxidants upon liver regeneration. This would have a therapeutic utilization in patients with liver problems.

How to cite this article:
Al Dohayan AD. The beneficial effect of α-tocopherol on liver regeneration after partial hepatectomy on rats. Saudi J Gastroenterol 1999;5:113-6

How to cite this URL:
Al Dohayan AD. The beneficial effect of α-tocopherol on liver regeneration after partial hepatectomy on rats. Saudi J Gastroenterol [serial online] 1999 [cited 2020 Jun 5];5:113-6. Available from: http://www.saudijgastro.com/text.asp?1999/5/3/113/33529


Liver regeneration, following a 70% hepatectomy and 15 minutes of normothermic hepatic ischemia, serves as an indirect functional test of the reperfused liver [1] . It has been shown that superoxide dismutase (SOD) (6mg/kg) and allopurinol (50mg/kg) have accelerated hepatocytic DNA synthesis without increasing the number or percentage of activated hepatocytes. However, the folinic acid has proved to be very effective, counteracting the deleterious effect of liver ischemia on hepatocytic regeneration [1] . Liver regeneration plays a key role in restoring the liver/body weight ratio after partial liver transplantation [2] . However, hepatic ischemia hinders the proliferative response of the hepatocytes. In many studies, different ways of improving the regenerating capacity of ischemic hepatocytes are tested [1],[2] . Cyclosporine A (hepatotrophic agent), SOD and folinic acid (antioxidants), administered during the ischemic period, have significantly increased these indices. The later drug has restored the regenerative response to the levels of normoperfused livers [1],[2] .

The hepatic regeneration following a two-thirds partial hepatectomy (PH) in the rat is a well-defined phenomenon that starts within a few minutes and leads, after a "latent phase" of ≈16h, to an increased synthesis of DNA followed by a first wave of mitosis. The mechanisms initiating and controlling this regenerative process, which restores quite precisely the original liver mass, remain poorly understood despite numerous studies performed in vivo and in vitro. In recent years, a great deal of emphasis has been placed on events occurring very rapidly after PH. Within a short time period, the hepatocytes should be modified (primed) by a reduction of the liver mass to become more responsive to various growth factors produced at a higher rate or, at least, present at a greater concentration [3],[4],[5] . Various modifications have indeed been observed quite early in the remaining lobes. For instance, a rise of the hepatocyte membrane potential has been detected as soon as 20 min after PH [6] . The increased expression of the protooncogene c-jun, c fos, and c-myc during the first hours [7], as well as the rapid DNA binding of nuclear factor KB [8],[9] , lends weight to the hypothesis that the proliferative response not only starts but is determined during this early phase [8],[9] . The role of positive feedback systems, such as the secondary production within the liver of growth factors amplifying initial stimuli, is well established [10],[11] whereas until now, negative controls have been mainly implicated in the cessation of proliferation after a few days.

The main objective of this study is to further investigate the role of oxygen free radicals using a well known antioxidant a-tocopherol (vitamin E) on liver regeneration after partial hepatectomy (PH).


   Materials and methods Top


α-tocopherol was purchased from Sigma Chemical Co., USA. Pure arachis oil was purchased from BDH Chemical Company, Poole, UK which is free from vitamin E. Thiopental was obtained from Biocheme GmbH, Vienna, Austria.

Animals

Male Wistar rats, weighing 150-200g, obtained from the College of Medicine animal house of King Saud University, and were housed five animals in a cage in a room at 22 + 1 °C. Rats were eating standard rat chow prior to the experiment and had free access to water and food ad libitum. The animals were divided into two groups (7 in each group). The first group received 600mgkg -1 of a-tocopherol intramuscularly daily for 3 weeks to reach the maximum concentration of a-tocopherol in the blood. The second group (control) received isometric arachis oil for 3 weeks, as been described previously [12]) . Three weeks after partial hepatectomy, the animal body weight was measured, animals were killed and liver was excised and weighed in both groups.

Surgical procedure

Thiopental was used as anaesthetic agent. Partial hepatectomy (PH) was performed at the end of the third week after initial treatment, according to the method described by Higgins and Anderson [13] . The animals were allowed to recover with free access to water and food after the surgical procedure and vitamin E was given daily. The animals were killed 3 weeks after PH. Body and liver weights were measured.


   Results Top


The effect of α-tocopherol (vitamin E) on body weight of partially hepatectomized rats was shown in [Table - 1]. The results illustrated that body weight increased but statistically insignificant compared to the control group. It also shows that an increase in the weight of the regenerated liver 4 weeks after partial hepatectomy compared to the control group which is statistically significant and p value is less than 0.05 using student t-test.


   Discussion Top


Liver has unique character since it has the ability to regenerate. This character is more obvious in normal regenerated liver. The regenerated liver can reach the normal mass within few weeks after hepatectomy. Active factors responsible in controlling the liver to regenerate is yet to be understood. In recent years, numerous studies have stressed on the evidence of the initial state of liver regeneration. Within short period of time, the hepatocyte primed by reduction of liver mass to become more stimulated to growth factors [3],[4],[5]

Surgery and hepatectomy are always associated with the ischaemia and reperfusion phenomenon. ischaemia and reperfusion is considered to be one of the major source of oxygen free radicals such as superoxide, hydrogen peroxide and hydroxyl radical. These oxygen free radicals have cytotoxic effect and cause inhibition of liver regeneration [14] . Oxygen free radicals, toxin and chemical can cause necrosis to the liver and can impair the mitotic activity of the hepatocyte [15] Foschi et al [14] reported the oxygen free radical generated by ischaemia reperfusion reduced the liver regeneration after partial hepatectomy in rats. Additionally, Oxygen free radicals, such as allopurinol, superoxide dismutase increase liver regeneration 3 days after hepatectomy in rats subjected to liver ischaemia and reperfusion.

The influence of superoxide dismutase and folinic acid upon liver regeneration was studied by Portugal et al [2] . They reported the significant hepatocyte regeneration capacity in hepatectomized rats. Rasolov et al. showed the positive stimulation of hepatocyte regeneration after isoproxihematran administration [16] . The influence of dietary vitamin E and santoquin on lipid peroxidation and liver regeneration in partially hepatectomized rats was studied by Gavino et al [17] has positive effect on liver regeneration. On the other hand, therapeutic administration of vitamin E to animal has statistical significance on liver regeneration of partially hepatectomized rats. Our results are in agreement with these studies and suggest that, α-tocopherol, a biological antioxidant can be beneficial in terms of increasing the regeneration rate of liver after partial hepatectomy in humans.


   Acknowledgement Top


The author wish to thank Professor Ali Sulaiman Al-Tuwaijri, Chairman of the Department of Physiology for his critical comments and suggestions in the writing of this manuscript. The author also want to thank Mr. Casimero Victoria and Mr. Sahipa Sabirin for their technical assistance and Mr. James Chu for typing the manuscript.

 
   References Top

1.Portugal V, Garcia-Alonso I, Bilbao J, Barcelo P, Mendez J. Effect of antioxidative therapy on regeneration of ischemic liver. Rev Esp Enfern Dig 1993;83:434-8.  Back to cited text no. 1    
2.Portugal V. Garcia-Alonso I, Barcelo P, Mendez J. Effect of ailopurinol, folinic acid, SOD and cyclosporine A on ischemic liver regeneration. Eur Surg Res 1995,27:69-76.  Back to cited text no. 2    
3.Fausto N. Mead JE. Regulation of liver growth: protooncogenes and transforming growth factors. Lab Invest 1989;60:4-13.  Back to cited text no. 3    
4.Lindroos PM. Zarnegar R, Michalopoulos GK. Hepatocyte growth factor (hepatopoietin A) rapidly increases in plasma before DNA synthesis and liver regeneration stimulated by partial hepatectomy and carbon tetrachloride administration. Hepatology 1991:13:743-50.  Back to cited text no. 4    
5.Michalopoulos GK. Liver regeneration: molecular mechanisms of growth control. FASEB J 1990:4:176-87.  Back to cited text no. 5    
6.De Hemptinne B. Lorge F, Kestens PJ. Lambotte L. Facteurs d'hyperpolarisation hepatocellulaire et regeneration apres hepatectomie partielle chez le rat. Acta Gastroenterol BeIg 1985;48:424-31.  Back to cited text no. 6    
7.Thompson NL, Mead JE, Braun L. Goyette M, Shank PR. Fausto N. Sequential protooncogene expression during rat liver regeneration. Cancer Res 1986;46:3111-7.  Back to cited text no. 7    
8.Cressman DE. Greenbaum LE. Haber BA. Taub R. Rapid activation of post-hepatectomy factor/nuclear factor KB in hepatocytes, a primary response in the regenerating liver. J Biol Chem 1994;269:30429-35.  Back to cited text no. 8    
9.Fitzgerald MJ, Webber EM, Donovan JR. Fausto N. Rapid DNA binding by nuclear factor KB in hepatocytes at the start of liver regeneration. Cell Growth Differ 1995:6:417-27.  Back to cited text no. 9    
10.Mead JE, Fausto N. Transforming growth factor a may be a physiological regulator of liver regeneration by means of an autocrine mechanism. Proc Nail Acad Sci USA 1989:86:1558-62.  Back to cited text no. 10    
11.Zarnegar R, DeFrances MC, Kost DP, Lindross P, Michalopoulos GK. Expression of hepatocyte growth factor mRNA in regenerating rat liver after partial hepatectomy. Biochem Biophys Res Common 1991:177:559-65.  Back to cited text no. 11    
12.AI-Tuwaijri AS, Al-Dohayan AD. Protective effects of a­tocopherol on gastric mucosal injury by ischaemia­reperfusion in rats. Med Sci Res 1995;23:627-8.  Back to cited text no. 12    
13.Higgins GM, Anderson RM. Experimental pathology of liver: restoration of liver of the white rat following partial surgical removal. Arch Pathol 1931;12:186-202.  Back to cited text no. 13    
14.Foschi D, Castoldi L, Lesma A, et al. Effects of ischaemia and reperfusion on liver regeneration in rats. Eur J Surg 1993;159:393-8.  Back to cited text no. 14  [PUBMED]  
15.Oberley L, Buettner GR. Role of superoxide dismutase in cancer: a review. Cancer Res 1979;39:1141-9.  Back to cited text no. 15    
16.Rasulov MM, Kuznetsov IG, Shakirova RG, et al. Isopropoxyhermatran - a stimulant of hepatocyte regeneration. Biull Eksp Biol Med 1993;115:69-71.  Back to cited text no. 16  [PUBMED]  
17.Gavino VC, Dillard CJ, Tappet AL. effect of dietary vitamin E and Santoquin on regenerating rat liver. Life Sci 1985;36:1771-7.  Back to cited text no. 17    

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Correspondence Address:
Abdullah D Al Dohayan
Department of Surgery, King Khalid University Hospital, P.O. Box 2925, Riyadh 11461
Saudi Arabia
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Source of Support: None, Conflict of Interest: None


PMID: 19864734

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