Skip to main content
SpringerLink
Log in

Protective Effects of Diallyl Sulfide, a Garlic Constituent, on the Warm Hepatic Ischemia–Reperfusion Injury in a Rat Model

  • Research Paper
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Purpose

The aim of this study is to evaluate the effects of diallyl sulfide (DAS) on the warm hepatic ischemia–reperfusion (IR) injury in a rat model.

Methods

Rats (n = 8–10/group) were subjected to sham operation or warm ischemia (1 h)-reperfusion (3 h) preceded by a single intraperitoneal dose (1.75 mmol/kg) of DAS or vehicle, and relevant biochemical parameters were monitored.

Results

Warm IR injury caused a significant increase in the plasma markers of liver injury, which was attenuated by DAS. The hepatoprotective effects of DAS were associated with significant reductions in lipid peroxidation markers and in situ generation of superoxide in the liver and increases in the glutathione levels of the liver and bile, suggestive of an antioxidant effect for DAS. Additionally, DAS caused an almost twofold increase in the protein expression of the liver heme oxygenase-1, an enzyme that confers cytoprotection against oxidative stress. Whereas the total cytochrome P450 remained unchanged, the protein levels and activity of CYP2E1, which plays an important role in the generation of reactive oxygen species, significantly decreased by DAS pretreatment.

Conclusions

DAS protects the liver from warm IR injury by reducing oxidative stress through, at least in part, induction of heme oxygenase-1 and inhibition of CYP2E1.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. G. Martinez-Mier, L. H. Toledo-Pereyra, and P. A. Ward. Adhesion molecules in liver ischemia and reperfusion. J. Surg. Res. 94:185–194 (2000).

    Article  PubMed  CAS  Google Scholar 

  2. H. Jaeschke, and J. J. Lemasters. Apoptosis versus oncotic necrosis in hepatic ischemia/reperfusion injury. Gastroenterology. 125:1246–1257 (2003).

    Article  PubMed  CAS  Google Scholar 

  3. S. N. Lichtman, and J. J. Lemasters. Role of cytokines and cytokine-producing cells in reperfusion injury to the liver. Semin. Liver Dis. 19:171–187 (1999).

    PubMed  CAS  Google Scholar 

  4. H. Jaeschke. Role of reactive oxygen species in hepatic ischemia–reperfusion injury and preconditioning. J. Invest. Surg. 16:127–140 (2003).

    Article  PubMed  Google Scholar 

  5. J. W. Kupiec-Weglinski, and R. W. Busuttil. Ischemia and reperfusion injury in liver transplantation. Transplant Proc. 37:1653–1656 (2005).

    Article  PubMed  CAS  Google Scholar 

  6. H. Jaeschke. Molecular mechanisms of hepatic ischemia–reperfusion injury and preconditioning. Am. J. Physiol. Gastrointest. Liver Physiol. 284:G15–G26 (2003).

    PubMed  CAS  Google Scholar 

  7. F. Serracino-Inglott, N. A. Habib, and R. T. Mathie. Hepatic ischemia–reperfusion injury. Am. J. Surg. 181:160–166 (2001).

    Article  PubMed  CAS  Google Scholar 

  8. A. Casillas-Ramirez, I. B. Mosbah, F. Ramalho, J. Rosello-Catafau, and C. Peralta. Past and future approaches to ischemia–reperfusion lesion associated with liver transplantation. Life Sci. 79:1881–1894 (2006).

    Article  PubMed  CAS  Google Scholar 

  9. N. Selzner, H. Rudiger, R. Graf, and P. A. Clavien. Protective strategies against ischemic injury of the liver. Gastroenterology. 125:917–936 (2003).

    Article  PubMed  CAS  Google Scholar 

  10. C. Borek. Antioxidant health effects of aged garlic extract. J Nutr. 131:1010S–1015S (2001).

    PubMed  CAS  Google Scholar 

  11. J. Imai, N. Ide, S. Nagae, T. Moriguchi, H. Matsuura, and Y. Itakura. Antioxidant and radical scavenging effects of aged garlic extract and its constituents. Planta Medica. 60:417–420 (1994).

    Article  PubMed  CAS  Google Scholar 

  12. K. Prasad, V. A. Laxdal, M. Yu, and B. L. Raney. Evaluation of hydroxyl radical-scavenging property of garlic. Mol. Cell Biochem. 154:55–63 (1996).

    Article  PubMed  CAS  Google Scholar 

  13. H. P. Chang, and Y. H. Chen. Differential effects of organosulfur compounds from garlic oil on nitric oxide and prostaglandin E2 in stimulated macrophages. Nutrition. 21:530–536 (2005).

    Article  PubMed  CAS  Google Scholar 

  14. H. P. Chang, S. Y. Huang, and Y. H. Chen. Modulation of cytokine secretion by garlic oil derivatives is associated with suppressed nitric oxide production in stimulated macrophages. J. Agric. Food Chem. 53:2530–2534 (2005).

    Article  PubMed  CAS  Google Scholar 

  15. C. C. Wu, L. Y. Sheen, H. W. Chen, W. W. Kuo, S. J. Tsai, and C. K. Lii. Differential effects of garlic oil and its three major organosulfur components on the hepatic detoxification system in rats. J. Agric. Food Chem. 50:378–383 (2002).

    Article  PubMed  CAS  Google Scholar 

  16. D. Taubert, R. Glockner, D. Muller, and E. Schomig. The garlic ingredient diallyl sulfide inhibits cytochrome P450 2E1 dependent bioactivation of acrylamide to glycidamide. Toxicol Lett. 164:1–5 (2006).

    Article  PubMed  CAS  Google Scholar 

  17. P. Thejass, and G. Kuttan. Antiangiogenic activity of diallyl sulfide (DAS). Int. Immunopharmacol. 7:295–305 (2007).

    Article  PubMed  CAS  Google Scholar 

  18. J. F. Brady, M. H. Wang, J. Y. Hong, F. Xiao, Y. Li, J. S. Yoo, S. M. Ning, M. J. Lee, J. M. Fukuto, J. M. Gapac et al. Modulation of rat hepatic microsomal monooxygenase enzymes and cytotoxicity by diallyl sulfide. Toxicol. Appl. Pharmacol. 108:342–354 (1991).

    Article  PubMed  CAS  Google Scholar 

  19. J. J. Hu, J. S. Yoo, M. Lin, E. J. Wang, and C. S. Yang. Protective effects of diallyl sulfide on acetaminophen-induced toxicities. Food Chem. Toxicol. 34:963–969 (1996).

    Article  PubMed  CAS  Google Scholar 

  20. S. L. Fanelli, G. D. Castro, E. G. de Toranzo, and J. A. Castro. Mechanisms of the preventive properties of some garlic components in the carbon tetrachloride-promoted oxidative stress. Diallyl sulfide; diallyl disulfide; allyl mercaptan and allyl methyl sulfide. Res. Commun. Mol. Pathol. Pharmacol. 102:163–174 (1998).

    PubMed  CAS  Google Scholar 

  21. P. Gong, B. Hu, and A. I. Cederbaum. Diallyl sulfide induces heme oxygenase-1 through MAPK pathway. Arch. Biochem. Biophys. 432:252–260 (2004).

    Article  PubMed  CAS  Google Scholar 

  22. L. Y. Sheen, C. K. Lii, S. F. Sheu, R. H. Meng, and S. J. Tsai. Effect of the active principle of garlic–diallyl sulfide-on cell viability, detoxification capability and the antioxidation system of primary rat hepatocytes. Food Chem. Toxicol. 34:971–978 (1996).

    Article  PubMed  CAS  Google Scholar 

  23. J. F. Brady, H. Ishizaki, J. M. Fukuto, M. C. Lin, A. Fadel, J. M. Gapac, and C. S. Yang. Inhibition of cytochrome P-450 2E1 by diallyl sulfide and its metabolites. Chem. Res. Toxicol. 4:642–647 (1991).

    Article  PubMed  CAS  Google Scholar 

  24. A. T. Canada, K. Stein, D. Martel, and W. D. Watkins. Biochemical appraisal of models for hepatic ischemia-reperfusion injury. Circ. Shock. 36:163–168 (1992).

    PubMed  CAS  Google Scholar 

  25. H. U. Spiegel, and R. Bahde. Experimental models of temporary normothermic liver ischemia. J. Invest Surg. 19:113–123 (2006).

    Article  PubMed  CAS  Google Scholar 

  26. I. H. Shaik, and R. Mehvar. Rapid determination of reduced and oxidized glutathione levels using a new thiol-masking reagent and the enzymatic recycling method: application to the rat liver and bile samples. Anal. Bioanal. Chem. 385:105–113 (2006).

    Article  PubMed  CAS  Google Scholar 

  27. H. Ukeda, S. Maeda, T. Ishii, and M. Sawamura. Spectrophotometric assay for superoxide dismutase based on tetrazolium salt 3¢-1-(phenylamino)-carbonyl-3, 4-tetrazolium]-bis(4-methoxy-6-nitro)benzenesulfonic acid hydrate reduction by xanthine-xanthine oxidase. Anal. Biochem. 251:206–209 (1997).

    Article  PubMed  CAS  Google Scholar 

  28. L. H. Johansson, and L. A. Borg. A spectrophotometric method for determination of catalase activity in small tissue samples. Anal. Biochem. 174:331–336 (1988).

    Article  PubMed  CAS  Google Scholar 

  29. R. Mateos, E. Lecumberri, S. Ramos, L. Goya, and L. Bravo. Determination of malondialdehyde (MDA) by high-performance liquid chromatography in serum and liver as a biomarker for oxidative stress. Application to a rat model for hypercholesterolemia and evaluation of the effect of diets rich in phenolic antioxidants from fruits. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 827:76–82 (2005).

    Article  PubMed  CAS  Google Scholar 

  30. V. Tong, T. K. Chang, J. Chen, and F. S. Abbott. The effect of valproic acid on hepatic and plasma levels of 15-F2t-isoprostane in rats. Free Radic. Biol. Med. 34:1435–1446 (2003).

    Article  PubMed  CAS  Google Scholar 

  31. B. G. Lake. Preparation and characterisation of microsomal fractions for studies on xenobiotic metabolism. In K. Snelland, and B. Mullock (eds.), Biochemical Toxicology, a Practical Approach, IRL, Oxford, UK, 1987, pp. 183–215.

    Google Scholar 

  32. R. Vuppugalla, and R. Mehvar. Hepatic disposition and effects of nitric oxide donors: rapid and concentration-dependent reduction in the cytochrome P450-mediated drug metabolism in isolated perfused rat livers. J. Pharmacol. Exp. Ther. 310:718–727 (2004).

    Article  PubMed  CAS  Google Scholar 

  33. T. Omura, and R. Sato. The carbon monoxide-binding pigment of the liver microsomes. Evidence for its hemoprotein nature. J. Biol. Chem. 239:2370–2378 (1964).

    PubMed  CAS  Google Scholar 

  34. R. Vuppugalla, R. B. Shah, A. P. Chimalakonda, C. W. Fisher, and R. Mehvar. Microsomal cytochrome P450 levels and activities of isolated rat livers perfused with albumin. Pharm. Res. 20:81–88 (2003).

    Article  PubMed  CAS  Google Scholar 

  35. Y. Minamiyama, S. Takemura, S. Toyokuni, S. Imaoka, Y. Funae, K. Hirohashi, T. Yoshikawa, and S. Okada. CYP3A induction aggravates endotoxemic liver injury via reactive oxygen species in male rats. Free Radic. Biol. Med. 37:703–712 (2004).

    Article  PubMed  CAS  Google Scholar 

  36. J. Belghiti, K. Hiramatsu, S. Benoist, P. Massault, A. Sauvanet, and O. Farges. Seven hundred forty-seven hepatectomies in the 1990s: an update to evaluate the actual risk of liver resection. J. Am. Coll. Surg. 191:38–46 (2000).

    Article  PubMed  CAS  Google Scholar 

  37. S. W. Ryter, J. Alam, and A. M. Choi. Heme oxygenase-1/carbon monoxide: from basic science to therapeutic applications. Physiol. Rev. 86:583–650 (2006).

    Article  PubMed  CAS  Google Scholar 

  38. H. Xue, H. Guo, Y. C. Li, and Z. M. Hao. Heme oxygenase-1 induction by hemin protects liver cells from ischemia/reperfusion injury in cirrhotic rats. World J. Gastroenterol. 13:5384–5390 (2007).

    PubMed  CAS  Google Scholar 

  39. R. Schmidt, E. Tritschler, A. Hoetzel, T. Loop, M. Humar, L. Halverscheid, K. K. Geiger, and B. H. Pannen. Heme oxygenase-1 induction by the clinically used anesthetic isoflurane protects rat livers from ischemia/reperfusion injury. Ann. Surg. 245:931–942 (2007).

    Article  PubMed  Google Scholar 

  40. X. D. Shen, B. Ke, Y. Zhai, F. Gao, R. W. Busuttil, G. Cheng, and J. W. Kupiec-Weglinski. Toll-like receptor and heme oxygenase-1 signaling in hepatic ischemia/reperfusion injury. Am. J. Transplant. 5:1793–1800 (2005).

    Article  PubMed  CAS  Google Scholar 

  41. H. Kato, F. Amersi, R. Buelow, J. Melinek, A. J. Coito, B. Ke, R. W. Busuttil, and J. W. Kupiec-Weglinski. Heme oxygenase-1 overexpression protects rat livers from ischemia/reperfusion injury with extended cold preservation. Am. J. Transplant. 1:121–128 (2001).

    Article  PubMed  CAS  Google Scholar 

  42. H. Su, G. M. van Dam, C. I. Buis, D. S. Visser, J. W. Hesselink, T. A. Schuurs, H. G. Leuvenink, C. H. Contag, and R. J. Porte. Spatiotemporal expression of heme oxygenase-1 detected by in vivo bioluminescence after hepatic ischemia in HO-1/Luc mice. Liver Transpl. 12:1634–1639 (2006).

    Article  PubMed  Google Scholar 

  43. K. Ito, S. Ikeda, T. Shibata, T. Yano, and S. Horikawa. Immunohistochemical analysis of heme oxygenase-I in rat liver after ischemia. Biochem. Mol. Biol. Int. 43:551–556 (1997).

    PubMed  CAS  Google Scholar 

  44. C. Chen, D. Pung, V. Leong, V. Hebbar, G. Shen, S. Nair, W. Li, and A. N. Kong. Induction of detoxifying enzymes by garlic organosulfur compounds through transcription factor Nrf2: effect of chemical structure and stress signals. Free Radic. Biol. Med. 37:1578–1590 (2004).

    Article  PubMed  CAS  Google Scholar 

  45. C. S. Yang, S. K. Chhabra, J. Y. Hong, and T. J. Smith. Mechanisms of inhibition of chemical toxicity and carcinogenesis by diallyl sulfide (DAS) and related compounds from garlic. J. Nutr. 131:1041S–1045S (2001).

    PubMed  CAS  Google Scholar 

  46. A. Zhukov, and M. Ingelman-Sundberg. Relationship between cytochrome P450 catalytic cycling and stability: fast degradation of ethanol-inducible cytochrome P450 2E1 (CYP2E1) in hepatoma cells is abolished by inactivation of its electron donor NADPH-cytochrome P450 reductase. Biochem. J. 340(Pt 2):453–458 (1999).

    Article  PubMed  CAS  Google Scholar 

  47. R. C. Zangar, D. R. Davydov, and S. Verma. Mechanisms that regulate production of reactive oxygen species by cytochrome P450. Toxicol. Appl. Pharmacol. 199:316–331 (2004).

    Article  PubMed  CAS  Google Scholar 

  48. V. G. Lee, M. L. Johnson, J. Baust, V. E. Laubach, S. C. Watkins, and T. R. Billiar. The roles of iNOS in liver ischemia-reperfusion injury. Shock. 16:355–360 (2001).

    Article  PubMed  CAS  Google Scholar 

  49. I. N. Hines, H. Harada, S. Flores, B. Gao, J. M. McCord, and M. B. Grisham. Endothelial nitric oxide synthase protects the post-ischemic liver: potential interactions with superoxide. Biomed. Pharmacother. 59:183–189 (2005).

    Article  PubMed  CAS  Google Scholar 

  50. J. S. Beckman, and W. H. Koppenol. Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and ugly. Am. J. Physiol. 271:C1424–C1437 (1996).

    PubMed  CAS  Google Scholar 

  51. H. Ohmori, D. K. Dhar, Y. Nakashima, M. Hashimoto, S. Masumura, and N. Nagasue. Beneficial effects of FK409, a novel nitric oxide donor, on reperfusion injury of rat liver. Transplantation. 66:579–585 (1998).

    Article  PubMed  CAS  Google Scholar 

  52. F. Langle, E. Roth, R. Steininger, S. Winkler, and F. Muhlbacher. Arginase release following liver reperfusion. Evidence of hemodynamic action of arginase infusions. Transplantation. 59:1542–1549 (1995).

    PubMed  CAS  Google Scholar 

  53. L. Chen, J. Y. Hong, E. So, A. H. Hussin, W. F. Cheng, and C. S. Yang. Decrease of hepatic catalase level by treatment with diallyl sulfide and garlic homogenates in rats and mice. J. Biochem. Mol. Toxicol. 13:127–134 (1999).

    Article  PubMed  CAS  Google Scholar 

  54. E. Niki, Y. Yoshida, Y. Saito, and N. Noguchi. Lipid peroxidation: mechanisms, inhibition, and biological effects. Biochem. Biophys. Res. Commun. 338:668–676 (2005).

    Article  PubMed  CAS  Google Scholar 

  55. M. Fukai, T. Hayashi, R. Yokota, T. Shimamura, T. Suzuki, M. Taniguchi, M. Matsushita, H. Furukawa, and S. Todo. Lipid peroxidation during ischemia depends on ischemia time in warm ischemia and reperfusion of rat liver. Free Radic. Biol. Med. 38:1372–1381 (2005).

    Article  PubMed  CAS  Google Scholar 

  56. D. R. Janero. Malondialdehyde and thiobarbituric acid-reactivity as diagnostic indices of lipid peroxidation and peroxidative tissue injury. Free Radic. Biol. Med. 9:515–540 (1990).

    Article  PubMed  CAS  Google Scholar 

  57. G. Sener, O. Sehirli, Y. Ipci, F. Ercan, S. Sirvanci, N. Gedik, and B. C. Yegen. Aqueous garlic extract alleviates ischaemia–reperfusion-induced oxidative hepatic injury in rats. J. Pharm. Pharmacol. 57:145–150 (2005).

    PubMed  CAS  Google Scholar 

Download references

Acknowledgement

The authors would like to thank Dr. Paul R. Lockman for assistance with fluorescence microscopy and Dr. Donald L. Montgomery from the University of Wyoming for histological studies.

Author information

Authors and Affiliations

  1. Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, 1300 S. Coulter, Amarillo, Texas, 79106, USA

    Imam H. Shaik, Jancy M. George, Thomas J. Thekkumkara & Reza Mehvar

Authors
  1. Imam H. Shaik
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jancy M. George
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Thomas J. Thekkumkara
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Reza Mehvar
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Reza Mehvar.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Shaik, I.H., George, J.M., Thekkumkara, T.J. et al. Protective Effects of Diallyl Sulfide, a Garlic Constituent, on the Warm Hepatic Ischemia–Reperfusion Injury in a Rat Model. Pharm Res 25, 2231–2242 (2008). https://doi.org/10.1007/s11095-008-9601-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-008-9601-8

KEY WORDS

Search

Navigation