Hepatotoxic effect of Rifampicin as an Anti-Tuberculosis drug on male Albino rat
Tuberculosis is one of the serious airborne infectious diseases. Rifampicin is commonly used as anti-tuberculosis drug which creates drug-induced hepatotoxicity. Physiologically, liver maintains metabolic homeostasis and also regulates the detoxification process. The study of rifampicin mediated hepatotoxicity had been performed on male albino rat after its oral administration with a dose of 50 mg/kg body weight/day for 14 days. Several biochemical markers like serum glutamate pyruvate tranaminase (AST), serum glutamate oxaloacetate transaminase (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), serum total protein, serum bilirubin, serum cholesterol were considered to evaluate the toxicity. Significant elevation of level of AST (115.89%), ALT (134.40%), ALP (46.15%), serum cholesterol (91%) and bilirubin content (119.44%) had been observed in treated group compared with control group. High level of MDA content as lipid peroxidation marker was also been noticed in drug induced group. Histopathological studies had shown the disintegrated hepatolobular structure with dilated central vein. All these findings indicated that the selected dose of rifampicin is hepatotoxic; proper monitoring and care are essential during the treatment of tuberculosis.
Keywords: rifampicin; hepatoxicity; anti-tuberculosis
2. Holt M, Ju C, Drug-induced liver injury, Handbook of Experimental Pharmacology. 2010; 196:3–27.
3. Stirnimann G, Kessebohm K, Lauterburg B, Liver injury caused by drugs: An update, Swiss Medical Weekly, 2010; 140:18.
4. Zhou Y, Yang L, Liao Z, He X, Zhou Y, Guo, H, Epidemiology of drug-induced liver injury in China: A systematic analysis of the Chinese literature including 21,789 patients, European Journal of Gastroenterology and Hepatology, 2013; 25:825–829.
5. World Health Organization (WHO), Tuberculosis, Fact Sheet No. 104, Reviewed March 2017, Available online: http://www.who.int/mediacentre/factsheets/fs104/en/ (accessed on 30 June 2017).
6. Singh J, Arora A, Garg P, Thakur V, Pande J, Tandon R, Antituberculosis treatment-induced hepatotoxicity: Role of predictive factors, Postgraduate Medical Journal, 1995; 71:359–362.
7. World Health Organization (WHO), Treatment of Tuberculosis Guidelines, 4th ed.; World Health Organization: Geneva, Switzerland, (2010); p. 46, ISBN 978-92-4-154783-3.
8. Steel MA, Burk RF, DesPrez RM, Toxic hepatitis with isoniazid and rifampin, Chest, 1991; 99: 467–471
9. Kim Ju-H, Nam SW, Kim SJ, Kwon OK, et al., Mechanism investigation of rifampicin-induced liver injury using comparative toxicoproteomics in mice, Inernational Journal of Molecular Science 2017; 18:1417. doi:10.3390/ijms18071417.
10. Sensi P, Margalith P, Timbal MT, Rifomycin, a new antibiotic preliminary report, Farmaco. Ed. Sci. 1959; 14: 146–147.
11. Balamurugan K, Vanithakumari G, Indra N, Effect of rifampicin on certain biochemical parameter in the liver of albino rats, The Internet Journal of Toxicology, 2008; 6 (1).
12. Nakajima A, Fukami T, Kobayashi Y, et al., Human arylacetamide deacetylase is responsible for deacetylation of rifamycins: rifampicin, rifabutin, and rifapentine, Biochemical Pharmacology, 2011; 82: 1747–1756.
13. Ramappa V, Aithal GP, Hepatotoxicity Related to Anti-tuberculosis Drugs: Mechanisms and Management, Journal of Clinical and Experimental Hepatology, 2013; 3 (1):37–49.
14. Campbell EA, Korzheva N, Mustaev A, Murakami K, Nair S, Goldfarb A, Darst SA, Structural Mechanism for Rifampicin Inhibition of Bacterial RNA Polymerase, Cell, 2001; 104(6):901–912.
15. Rana SV, Pal R, Vaiphie K, Singh K, Effect of different oral doses of isoniazid-rifampicin in rats, Molecular and Cellular Biochemistry. 2006; 289:39–47. doi: 10.1007/s11010-006-9145-3.
16. Low PA, Robertson D, Kaufmann H, Singer W, Biaggioni I, et al., Efficacy and safety of rifampicin for multiple system atrophy: a randomised, double-blind, placebo-controlled trial, Lancet Neurology, 2014; 13 (3):268-275. doi:https://doi.org/10.1016/S1474-4422(13)70301-6
17. Tripathy S, Das S, Chakraborty S P, Sahu SK, Pramanik P, Roy S, Synthesis, characterization of chitosan-tripolyphosphate conjugated chloroquine nanoparticle and its in vivo anti-malarial efficacy against rodent parasite: A dose and duration dependent approach, International Journal of Pharmaceutics, 2012; 434: 292–305.
18. Dassarma B, Nandi DK, Gangopadhyay S, Samanta S, Hepatoprotective effect of food preservatives (butylated hydroxyanisole, butylated hydroxytoluene) on carbon tetrachloride-induced hepatotoxicity in rat, Toxicology Reports, 2018; 5:31–37.
19. Ohkawa H, Ohishi N, Yagi K, Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction, Analytical Biochemistry, 1979; 95: 351–358.
20. Devarbhavi H, Singh R, Patil M, Sheth K, Adarsh CK, Balaraju G, Outcome and determinants of mortality in 269 patients with combination anti-tuberculosis drug-induced liver injury, Journal of Gastroenterology and Hepatology, 2013; 28:161–167.
21. Huang JH, Zhang C, Zhang DG, Li L, Chen X, Xu DX, Rifampicin-induced hepatic lipid accumulation: Association with up-regulation of peroxisome proliferator-activated receptor gamma in mouse liver, PLoS ONE, 2016; 11:e0165787.
22. Brewer CT, Chen T, PXR variants: The impact on drug metabolism and therapeutic responses, Acta Pharmaceutica Sinica B, 2016; 6:441–449.
23. Yan J, Xie W, A brief history of the discovery of PXR and CAR as xenobiotic receptors, Acta Pharmaceutica Sinica B, 2016; 6:450–452.
24. Chowdhury A, Santra A, Bhattacharjee K, Ghatak S, Saha DR, Dhali GK, Mitochondrial oxidative stress and permeability transition in isoniazid and rifampicin induced liver injury in mice, Journal of Hepatology, 2006; 45:117–126.
25. Jussi SJ, David CL, Robert JM, Steven S, John JA, et al., An Official ATS Statement: Hepatotoxicity of Antituberculosis Therapy, American Journal of Respiratory and Critical Care Medicine, 2006; 174:935–952. doi: 10.1164/rccm.200510-1666ST
26. Byrne JA, Strautnieks SS, Mieli-Vergani G, Higgins CF, Linton KJ, Thompson RJ, The human bile salt export pump: characterization of substrate specificity and identification of inhibitors, Gastroenterology, 2002; 123:1649–1658.
27. Grosset J, Leventis S, Adverse effects of rifampin, Review of Infectious Disease, 1983; 5:S440–S450.
28. Capelle P, Dhumeaux D, Mora M, Feldmann G, Berthelot P, Effect of rifampicin on liver function in man, Gut, 1972; 13:366–371.
29. Greenber, AS, Egan JJ, Wek SA, Garty NB, Blanchette-Mackie E, Londos C, Perilipin, a major hormonally regulated adipocyte-specific phosphoprotein associated with the periphery of lipid storage droplets, Journal of Biological Chemistry, 1991; 266:11341–11346.
30. Londos C, Brasaemle DL, Schultz CJ, Segrest JP, Kimmel AR, Perilipins, ADRP, and other proteins that associate with intracellular neutral lipid droplets in animal cells, Seminars in Cell and Developmental Biology, 1999; 10:51–58.
31. Brasaemle DL, Subramanian V, Garcia A, Marcinkiewicz A, Rothenberg A, Perilipin a and the control of triacylglycerol metabolism, Molecular and Cellular Biochemistry, 2009; 326:15–21.
32. Dalen KT, Schoonjans K, Ulven SM, Weedon-Fekjaer MS, Bentzen TG, Koutnikova H, Auwerx J, Nebb HI, Adipose tissue expression of the lipid droplet–associating proteins S3–12 and perilipin is controlled by peroxisome proliferator—Activated receptor, Diabetes, 2004; 53: 1243–1252.
33. Menzies D, Dion MJ, Rabinovitch B, et al., Treatment completion and costs of a randomized trial of rifampin for 4 months versus isoniazid for 9 months, American Journal Respiratory Critical Care Mediccine, 2004; 170:445–449.
34. Pandit A, Sachdeva T, Bafna P, Drug-Induced Hepatotoxicity: A Review, Journal of Applied Pharmaceutical Science, 2012; 02 (05):233-243
35. Sarma GR, Immanuel C, Kailasam S, et al., Rifampin-induced release of hydrazine from isoniazid. A possible cause of hepatitis during treatment of tuberculosis with regimens containing isoniazid and rifampin, American Review of Respiratory Disease, 1986; 133:1072–1075.
36. Ishak K, Baptista A, Bianchi L, Callea F, et al., Histological grading and staging of chronic hepatitis, Journal of Hepatology, 1995; 22(6):696-9.
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