Orlistat is a safe and effective drug to treat obesity by acting as a pancreatic and gastric lipase inhibitor, resulting in reduction in fat absorption. There is also concern that it may be linked with an increased threat of serious hepatic incidents. The present work was carried out to study the effect of orlistat on the histological, immunohistochemical and electron microscopic structure of the liver in the adult male albino rats and the possible protective role of β-carotene administration. Forty adult albino rats were subjected to experiment for two weeks as follows: group 1 (control), group II, each animal received 0.52 mg/kg bw/day β-Carotene, group III, each animal received orlistat 32 mg/kg/day, and group IV received β-Carotene, 1hour before the administration of orlistat at same dose of group II & III. The liver from each animal was dissected out and processed for histological, (light and electron microscopic study). The result of Hep-Par1 for immunohistochemistry was statistically analyzed. The results showed that orlistat treated group displayed variable disturbance of liver architecture, from dilatation, congested central and portal veins, branching of bile ductules, mononuclear cellular infiltration, areas of hemorrhages, cytoplasmic vacuolation and pyknotic nuclei. The most obvious changes were that degenerative changes in hepatocytes led to depletion of glycogen content of hepatocytes. Hep Par-1 revealed a wide area of negative immune expression around the central vein and in some hepatocytes. Other hepatocytes expressed weak reaction. Ultrastructure examination displayed hepatocytes with swollen mitochondria and others with an electron-dense matrix. The combined treatment of β-Carotene and orlistat led to a marked improvement in most of the previously mentioned changes. It was concluded that orlistat-induced hepatic toxicity. Thus, clinicians should cautiously monitor their patients for signs of hepatic dysfunction. Using an antioxidant such as β-Carotene decreased the toxicity of orlistat.
References
[1]
Kang, J.G. and Park, C.Y. (2012) Anti-Obesity Drugs: A Review about Their Effects and Safety. Diabetes & Metabolism Journal, 36, 13-25.
https://doi.org/10.4093/dmj.2012.36.1.13
[2]
Heal, D.J., Gosden, J. and Smith, S.L. (2012) What Is the Prognosis for New Centrally-Acting Anti-Obesity Drugs? Neuropharmacology, 63,132-146.
https://doi.org/10.1016/j.neuropharm.2012.01.017
[3]
Zhi, J., Melia, A. T., Funk, C., Viger-Chougnet, A., Hopfgartner, G. and Lausecker, B. (1996) Metabolic Profiles of Minimally Absorbed Orlistat in Obese/Overweight Volunteers. The Journal of Clinical Pharmacology, 36, 1006-1011.
https://doi.org/10.1177/009127009603601104
[4]
Sjostrom, L., Rissanen, A., Andersen, T., Boldrin, M., Golay, A. and Koppeschaar, H.P. (1998) Randomised Placebo-Controlled Trial of Orlistat for Weight Loss and Prevention of Weight Regain in Obese Patients. European Multicentre Orlistat Study Group. The Lancet, 352, 167-172.
https://doi.org/10.1016/S0140-6736(97)11509-4
[5]
Hogan, S., Fleury, A., Hadvary, P., Lengsfeld, H., Meier, M.K. and Triscari, J. (1987) Studies on the Antiobesity Activity of Tetrahydrolipstatin, A Potent and Selective Inhibitor of Pancreatic Lipase. International Journal of Obesity (London), 11, 35-42.
[6]
Guerciolini, R. (1997) Mode of Action of Orlistat. International Journal of Obesity and Related Metabolic Disorders, 21, S12-S23.
[7]
Torgerson, J.S., Hauptman, J., Boldrin, M.N. and Sjostrom, L. (2004) XENical in the Prevention of Diabetes in Obese Subjects (XENDOS) Study: A randomized Study of Orlistat as an Adjunct to Lifestyle Changes for the Prevention of Type 2 Diabetes in Obese Patients. Diabetes Care, 27, 155-161. https://doi.org/10.2337/diacare.27.1.155
[8]
Kelley, D.E., Kuller, L.H., McKolanis, T.M., Harper, P., Mancino, J. and Kalhan, S. (2004) Effects of Moderate Weight Loss and Orlistat on Insulin Resistance, Regional Adiposity, and Fatty Acids in Type 2 Diabetes. Diabetes Care, 27, 33-40.
https://doi.org/10.2337/diacare.27.1.33
[9]
Hussein, O., Grosovski, M., Schlesinger, S., Szvalb, S. and Assy, N. (2007) Orlistat Reverses Fatty Infiltration and Improves Hepatic Fibrosis in Obese Patients with Nonalcoholic Steatohepatitis (NASH). Digestive Diseases and Sciences, 52, 2512-2519.
https://doi.org/10.1007/s10620-006-9631-1
[10]
Siebenhofer, A., Horvath, K., Jeitler, K., Berghold, A., Stich, A.K. and Matyas, E. (2009) Long-Term Effects of Weight-Reducing Drugs in Hypertensive Patients. Cochrane Database of Systematic Reviews, 3, CD007654.
[11]
Muls, E., Kolanowski, J., Scheen, A. and L Van Gaal ObelHyx Study Group (2001) The Effects of Orlistat on Weight and on Serum Lipids in Obese Patients with Hypercholesterolemia: A Randomized, Double Blind, Placebo-Controlled Multicentre Study. International Journal of Obesity, 25, 1713-1721.
https://doi.org/10.1038/sj.ijo.0801814
[12]
Song, J., Ruan, X., Gu, M., Wang, L., Wang, H. and Mueck, A.O. (2017) Effect of Orlistat or Metformin in Overweight and Obese Polycystic Ovary Syndrome Patients with Insulin Resistance. Gynecological Endocrinology, 24, 1-5.
[13]
Caner, M., Dogruman, H., Taskin, E., Kandil, A. and Demirci, C. (2005) Effects of Orlistat and Its Relationship with Nitric Oxide in the Small Intestinal Mucosa. Chinese Journal of Physiology, 48, 217-222.
[14]
Filippatos, T.D., Derdemezis, C.S, Gazi, I.F., Nakou, E.S., Mikhailidis, D.P. and Elisaf, M.S. (2008) Orlistat-Associated Adverse Effects and Drug Interactions: A Critical Review. Drug Safety, 31, 53-65.
https://doi.org/10.2165/00002018-200831010-00005
[15]
Kose, M., Emet, S., Akpınara, T.S. and Ilhanc, M. (2015) An Unexpected Result of Obesity Treatment: Orlistat-Related Acute Pancreatitis. Case Reports in Gastroenterology, 9, 152-155. https://doi.org/10.1159/000430433
[16]
Padwal, R.S. and Majumdar, S.R. (2007) Drug Treatments for Obesity: Orlistat, Sibutramine, and Rimonabant. The Lancet, 369, 71-77.
https://doi.org/10.1016/S0140-6736(07)60033-6
[17]
Saini, R.K., Nile, S.H. and Park, S.W. (2015) Carotenoids from Fruits and Vegetables: Chemistry, Analysis, Occurrence, Bioavailability and Biological Activities. Food Research International, 76, 735-750.
https://doi.org/10.1016/j.foodres.2015.07.047
[18]
Fukuzawa, K., Inokami, Y. and Tokumura, A. (1998) Rate Constants for Quenching Singlet Oxygen and Activities for Inhibiting Lipid Peroxidation of Carotenoids and Alpha-Tocopherol in Liposomes. Lipids, 33, 751-756.
https://doi.org/10.1007/s11745-998-0266-y
[19]
Fraser, P.D. and Bramley, P.M. (2004) The Biosynthesis and Nutritional Uses of Carotenoids. Progress in Lipid Research, 43, 228-265.
https://doi.org/10.1016/j.plipres.2003.10.002
[20]
Van Poppel, G. (1993) Carotenoids and Cancer: An Update with Emphasis on Human Intervention Studies. European Journal of Cancer, 29A, 1335-1344.
https://doi.org/10.1016/0959-8049(93)90087-V
[21]
Handelman, G.J., van Kuijk, F.J.G.M., Chatterjee, A. and Krinsky, N.I. (1991) Characterization of Products Formed during the Autoxidation of β-Carotene. Free Radical Biology & Medicine, 10, 427-437.
https://doi.org/10.1016/0891-5849(91)90051-4
[22]
Chu, P.G., Ishizawa, S., Wu, E. and Weiss, L.M. (2002) Hepatocyte Antigen as a Marker of Hepatocellular Carcinoma: An Immunohistochemical Comparison to Carcinoembryonic Antigen, CD10, and Alpha-Fetoprotein. The American Journal of Surgical Pathology, 26, 978-988.
https://doi.org/10.1097/00000478-200208000-00002
[23]
Peng, H.C., Chen, Y.L., Yang, S.Y., et al. (2013) The Antiapoptotic Effects of Different Doses of β-Carotene in Chronic Ethanol-Fed Rats. Hepatobiliary Surgery and Nutrition, 2, 132-141.
[24]
Cruz Hernandez, C., Oliveira, M., Pescia, G., Moulin, J., Masserey Elmelegy, I., Dionisi, F. and Destaillats, F. (2010) Lipase Inhibitor Orlistat Decreases Incorporation of Eicosapentaenoic and Docosahexaenoic Acids in Rat Tissues. Nutrition Research, 30, 134-140. https://doi.org/10.1016/j.nutres.2009.12.001
[25]
Paget, G.E. and Branes, G.M. (1964) Toxicity Tests. In: Laurence, D.R. and Bacharach, A.L., Eds., Evaluation of Drug Activities: Pharmacometrics, Vol. 1, 2nd Edition, Academic Press, London. https://doi.org/10.1016/B978-1-4832-2845-7.50012-8
[26]
Bancroft, J.D. and Gamble, M. (2013) Theory and Practice of Histological Techniques. 7th Edition, Churchill Livingstone of Elsevier, Philadelphia, 172-186.
[27]
Bancroft, J.D. and Stevens, A. (1996) Theory and Practice of Histotechnological Techniques. 4th Edition, Churchill Livingstone, New York.
[28]
Abdelrahman, A.E., Abdel-Aziz, H.R. and Hegazy, A.A. (2015) Immunohistochemical Distinction of Hepatocellular Carcinoma Using Arginase-1, Hepatocyte Paraffin Antigen-1 and Glypican-3. Journal of Tumor, 4, 359-366.
https://doi.org/10.17554/j.issn.1819-6187.2016.04.75
[29]
AL-Rawi, M.M. (2007) Effect of Trifolium sp. Flowers Extracts on the Status of Liver Histology of STZ-Induced Diabetic Rats. Saudi Journal of Biological Sciences, 14, 21-28.
[30]
Atiq, M., Davis, J.C., Lamps, L.W., Beland, S.S. and Rose, J.E. (2009) Amiodarone Induced Liver Cirrhosis. Report of Two Cases. Journal of Gastrointestinal and Liver Diseases, 18, 233-235.
[31]
Bu, D.X., Erl, W., De Martin, R., Hansson, G.K. and Yan, Z.-Q. (2005) IKK β-Dependent NF-κB Pathway Controls Vascular Inflammation and Intimal Hyperplasia. The FASEB Journal, 19, 1293-1295. https://doi.org/10.1096/fj.04-2645fje
[32]
U.S. Food and Drug Administration (2010) FDA Drug Safety Communication. Completed Safety Review of Xenical/Alli (orlistat) and Severe Liver Injury.
http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsand
Providers/ucm213038.htm
[33]
LeSage, G., Glaser, S. and Alpini, G. (2001) Regulation of Cholangiocyte Proliferation. Liver, 21, 73-80. https://doi.org/10.1034/j.1600-0676.2001.021002073.x
[34]
Jang, S.H., Lim, J.W. and Kim, H.B. (2009) Carotene Inhibits Helicobacter Pylori-Induced Expression of Inducible Nitric Oxide Synthase and Cyclooxygenase-2 in Human Gastric Epithelial AGS cells. Journal of Physiology and Pharmacology, 60, 131-137.
[35]
Sakr, S.A., Abdel Samei, H.A. and Soliman, M.E. (2004) Exploring Hepatotoxicity of Benomyl. Histological and Histochemical Study on Albino Rats. Journal of Medical Sciences, 4, 77-83. https://doi.org/10.3923/jms.2004.77.83
[36]
Gopumadhavan, S., Mohammed, R., Azeemuddin, M. and Mitra, S.K. (2008) Ameliorative Effect of Partysmart in Rat Model of Alcoholic Liver Disease. Indian Journal of Experimental Biology, 46, 132-137.
[37]
Shehata, A.S., Mohamed, Z.A., Abd El-Haleem, M.R. and Samak, M.A. (2013) Effects of Exposure to Plasticizers Di-(2-Ethylhexyl) Phthalate and Trioctyltrimellitate on the Histological Structure of Adult Male Albino Rats’ Liver. Journal of Clinical Toxicology, 3, 4.
[38]
Pradeep, K., Raj Mohan, C.V., Gobianand, K. and Karthikeyan, S. (2010) Protective Effect of Cassia fistula Linn. on Diethylnitrosamine Induced Hepatocellular Damage and Oxidative Stress in Ethanol Pretreated Rats. Biological Research, 43, 113-125.
https://doi.org/10.4067/S0716-97602010000100013
[39]
Aliev, G., Palacios, H.H., Gasimov, E., Obrenovich, M.E., Morales, L., Leszek, J., et al. (2010) Oxidative Stress Induced Mitochondrial Failure and Vascular Hypoperfusion as a Key Initiator for the Development of Alzheimer Disease. Pharmaceuticals, 3, 158-187. https://doi.org/10.3390/ph3010158
[40]
Lu, X., Hamilton, J.A., Shen, J., Pang, T., Jones, D.L. and Potter, R.F. (2006) Role of Tumor Necrosis Factor-Alpha in Myocardial Dysfunction and Apoptosis during Hind Limb Ischemia and Reperfusion. Critical Care Medicine, 34, 484-491.
https://doi.org/10.1097/01.CCM.0000199079.64231.C1
[41]
Johar, D., Roth, J.C., Bay, G.H., Walker, J.N., Kroczak, T.J. and Los, M. (2004) Inflammatory Response, Reactive Oxygen Species, Programmed (Necrotic-Like and Apoptotic) Cell Death and Cancer. Roczniki Akademii Medycznej W Bialymstoku, 49, 31-39.
[42]
Ohkuwa, T., Sato, K. and Naoi, M. (1995) Hydrozyl Radical Formation in Diabetic Rat Induced by Streptozotocin. Life Sciences, 56, 1789-1798.
https://doi.org/10.1016/0024-3205(95)00150-5
[43]
Lin, W.T., Huang, C.C., Lin, T.J., et al. (2009) Effects of Beta Carotene on Antioxidant Status in Rats with Chronic Alcohol Consumption. Cell Biochemistry and Function, 27, 344-350. https://doi.org/10.1002/cbf.1579
[44]
Das, R., Das, A., Roy, A., Kumari, U., Bhattacharya, S. and Haldar, P.K. (2015) β-Carotene Ameliorates Arsenic-Induced Toxicity in Albino Mice. Biological Trace Element Research, 164, 226-233. https://doi.org/10.1007/s12011-014-0212-4
[45]
Ahmed, S., Leo, M.A. and Lieber, C.S. (1994) Interactions between Alcohol and Beta-Carotene in Patients with Alcoholic Liver Disease. The American Journal of Clinical Nutrition, 60, 430-436. https://doi.org/10.1093/ajcn/60.3.430
