ACUTE TOXICITY TESTING OF NEWLY DISCOVERED POTENTIAL ANTIHEPATITIS B VIRUS AGENTS OF PLANT ORIGIN
Keywords:Hepatitis B virus, Isoquinoline alkaloids, Antiviral, Cytotoxicity, Acute toxic class method, Organization for Economic Cooperation and Development 423
Objective: Our previous studies indicate that alkaloids could be developed as potential antihepatitis B agents. In the present study, we investigated the in vitro antihepatitis B virus (HBV) activity and in vivo acute oral toxicity of three isoquinoline alkaloids [-(-) Canadine, Corydadine, and Berberine] obtained from Fumaria and Corydalis species. The compounds were selected based on their therapeutic indexes calculated previously in vitro.
Methods: The antiviral activity and cytotoxicity of selected isoquinoline alkaloids were evaluated in vitro in HepG2 cells. In vivo, acute oral toxicity was performed in female mice following the Organization for Economic Cooperation and Development test guideline-423 (acute toxicity class method).
Results: The selected agents have shown high antiviral activity against HBV and low cytotoxicity in vitro. The results obtained from an acute oral toxicity study revealed that the LD50 of all the test compounds was >2000 mg/kg when administered orally to mice. All the tested compounds fall under the category 5 (unclassified) according to the Globally Harmonized System, with a LD50 value >2000 mg/kg when orally administered to mice.
Conclusion: The results of the study revealed that OR-13 and MNAD can be studied further and can be developed as antihepatitis B drugs.
Agarwal N, Naik S, Aggarwal R, Singh H, Somani SK, Kini D, et al. Occult hepatitis B virus infection as a cause of cirrhosis of liver in a region with intermediate endemicity. Indian J Gastroenterol 2003;22:127-31.
Lewis S, Roayaie S, Ward SC, Shyknevsky I, Jibara G, Taouli B. Hepatocellular carcinoma in chronic hepatitis C in the absence of advanced fibrosis or cirrhosis. AJR Am J Roentgenol 2013;200:W610-6.
Sun P, Yang X, He RQ, Hu QG, Song ZF, Xiong J, et al. Antiviral therapy after curative treatment of hepatitis B/C virus-related hepatocellular carcinoma: A systematic review of randomized trials. Hepatol Res 2014;44:259-69.
Idilman R, Cinar K, Seven G, Bozkus Y, Elhan A, Bozdayi M, et al. Hepatitis B surface antigen seroconversion is associated with favourable long-term clinical outcomes during lamivudine treatment in HBeAg-negative chronic hepatitis B patients. J Viral Hepat 2012;19:220-6.
Li SY, Qin L, Zhang L, Song XB, Zhou Y, Zhou J, et al. Molecular epidemical characteristics of lamivudine resistance mutations of HBV in southern China. Med Sci Monit 2011;17:PH75-80.
Han Y, Zhang Y, Mei Y, Wang Y, Liu T, Guan Y, et al. Analysis of hepatitis B virus genotyping and drug resistance gene mutations based on massively parallel sequencing. J Virol Methods 2013;193:341-7.
McGonigal KH, Bajjoka IE, Abouljoud MS. Tenofovir-emtricitabine therapy for the prevention of hepatitis B recurrence in four patients after liver transplantation. Pharmacotherapy 2013;33:e170-6.
Jenh AM, Pham PA. Tenofovir disoproxil fumarate in the treatment of chronic hepatitis B. Expert Rev Anti Infect Ther 2010;8:1079-92.
Billioud G, Pichoud C, Puerstinger G, Neyts J, Zoulim F. The main hepatitis B virus (HBV) mutants resistant to nucleoside analogs are susceptible in vitro to non-nucleoside inhibitors of HBV replication. Antiviral Res 2011;92:271-6.
Souto AL, Tavares JF, da Silva MS, Diniz Mde F, de Athayde-Filho PF, Barbosa Filho JM. Anti-inflammatory activity of alkaloids: An update from 2000 to 2010. Molecules 2011;16:8515-34.
Aiello A, Fattorusso E, Imperatore C, Irace C, Luciano P, Menna M, et al. Zorrimidazolone, a bioactive alkaloid from the non-indigenous mediterranean stolidobranch Polyandrocarpa zorritensis. Mar Drugs 2011;9:1157-65.
Aljofan M, Netter HJ, Aljarbou AN, Hadda TB, Orhan IE, Sener B, et al. Anti-hepatitis B activity of isoquinoline alkaloids of plant origin. Arch Virol 2014;159:1119-28.
Sells MA, Zelent AZ, Shvartsman M, Acs G. Replicative intermediates of hepatitis B virus in HepG2 cells that produce infectious virions. J Virol 1988;62:2836-44.
Hamid HA, Yahaya IH. Cytotoxicity of Clinacanthus nutans extracts on human hepatoma (HEPG2) cell line. Int J Pharm Pharm Sci 2016;8:293-5.
Kesavanarayanan KS, Sathiya S, Kalaivani P, Ranju V, Sunil AG, Saravana Babu C, et al. DIA-2, a polyherbal formulation ameliorates hyperglycemia and protein-oxidation without increasing the body weight in Type II diabetic rats. Eur Rev Med Pharmacol Sci 2013;17:356-69.
Santosh NB, Pravin DC. Acute and sub-acute oral toxicity assessment of the polyherbal formulation in albino wister rats. Int J Pharm Pharm Sci 2016;8:311-6.
OECD Guidelines for the Testing of Chemicals and Section 4: Health Effects Test No. 423: Acute Oral Toxicity-Acute Toxic Class Method. Paris: OECD Publishing; 2002.
Monga M, Sausville EA Developmental therapeutics program at the NCI: Molecular target and drug discovery process. Leukemia 2002;16:520-6.
Lorke D. A new approach to practical acute toxicity testing. Arch Toxicol 1983;54:275-87.
Chinedu E, Arome D, Ameh FS. A new method for determining acute toxicity in animal models. Toxicol Int 2013;20:224-6.
Parasuraman S. Toxicological screening. J Pharmacol Pharmacother 2011;2:74-9.
Bruce RD. An up-and-down procedure for acute toxicity testing. Fundam Appl Toxicol 1985;5:151-7.
How to Cite
The publication is licensed under CC By and is open access. Copyright is with author and allowed to retain publishing rights without restrictions.