Lamidi W B Olaniyan1, Emmanuel N Maduagwu2, Olalekan Wasiu Akintunde3, Oladimeji O Oluwayelu4, Bartholomew I C Brai5. 1. Biochemistry Department, Faculty of Basic Medical Sciences, Ladoke Akintola University of Technology, Ogbomoso, Nigeria. 2. Biochemistry Department, College of Medicine, University of Ibadan, Ibadan, Nigeria. 3. Anatomy Department, Faculty of Basic Medical Sciences, Ladoke Akintola University of Technology Ogbomoso, Ogbomoso, Nigeria. 4. Veterinary Microbiology and Parasitology Department, Faculty of Veterinary Medicine, University of Ibadan, Ibadan, Nigeria. 5. Molecular Biology and Biotechnology Division, Nigerian Institute of Medical Research Lagos, Lagos, Nigeria.
Abstract
BACKGROUND: Lamivudine is a nucleoside analogue antiretroviral drug, known for its low toxicity at clinically prescribed dose. However, the toxicity or mechanism of toxicity and target tissue effects during prolonged administration of higher doses were hardly given sufficient laboratory attention. AIM: The present work was designed to investigate the biochemical and histopathological changes in the liver of rat administered with prolonged doses of lamivudine. MATERIAL AND METHODS: Lamivudine in multiple doses of five ranging from 4 mg/kg to 2500 mg/kg were administered, in vitro, by injection into the air-sac of 10-day old fertile embryonated eggs of Gallus domesticus. Also, female rats of the Wistar strain received oral doses, up to 500 mg/kg singly or repeatedly for 15 or 45 days, respectively. Spectrophotometric techniques were employed to monitor activities of the aminotransferases (ALT and AST), γ-glutamyltransferase (GGT) and total protein concentration in serum while activities of glutathione S-transferase (GST), GGT and superoxide dismutase (SOD) as well as concentrations of malondialdehyde (MDA) and protein were determined in liver. Histopathological studies were carried out on liver. Data were analysed using ANOVA and were considered significant when p < 0.05. RESULTS: The LD50 for the drug calculated from the incubation experiment was 427 mg/kg. Total serum protein concentration significantly reduced while enzymes activities significantly increased at 500 mg/kg only among the repeat-dosed rats. Hepatic GGT, GST and SOD activities as well as MDA concentration were significantly elevated at 20 mg/kg. Histopathological studies showed multifocal lymphoid cell population in the liver sinusoid of the chicken and hydropic degeneration of hepatocytes were recorded among rats repeatedly exposed to the drug respectively at doses ≥ 100 mg/kg. CONCLUSION: Lamivudine toxicity in rat liver appeared to be mediated by oxidative stress.
BACKGROUND:Lamivudine is a nucleoside analogue antiretroviral drug, known for its low toxicity at clinically prescribed dose. However, the toxicity or mechanism of toxicity and target tissue effects during prolonged administration of higher doses were hardly given sufficient laboratory attention. AIM: The present work was designed to investigate the biochemical and histopathological changes in the liver of rat administered with prolonged doses of lamivudine. MATERIAL AND METHODS:Lamivudine in multiple doses of five ranging from 4 mg/kg to 2500 mg/kg were administered, in vitro, by injection into the air-sac of 10-day old fertile embryonated eggs of Gallus domesticus. Also, female rats of the Wistar strain received oral doses, up to 500 mg/kg singly or repeatedly for 15 or 45 days, respectively. Spectrophotometric techniques were employed to monitor activities of the aminotransferases (ALT and AST), γ-glutamyltransferase (GGT) and total protein concentration in serum while activities of glutathione S-transferase (GST), GGT and superoxide dismutase (SOD) as well as concentrations of malondialdehyde (MDA) and protein were determined in liver. Histopathological studies were carried out on liver. Data were analysed using ANOVA and were considered significant when p < 0.05. RESULTS: The LD50 for the drug calculated from the incubation experiment was 427 mg/kg. Total serum protein concentration significantly reduced while enzymes activities significantly increased at 500 mg/kg only among the repeat-dosed rats. Hepatic GGT, GST and SOD activities as well as MDA concentration were significantly elevated at 20 mg/kg. Histopathological studies showed multifocal lymphoid cell population in the liver sinusoid of the chicken and hydropic degeneration of hepatocytes were recorded among rats repeatedly exposed to the drug respectively at doses ≥ 100 mg/kg. CONCLUSION:Lamivudinetoxicity in rat liver appeared to be mediated by oxidative stress.
Authors: C L Lai; R N Chien; N W Leung; T T Chang; R Guan; D I Tai; K Y Ng; P C Wu; J C Dent; J Barber; S L Stephenson; D F Gray Journal: N Engl J Med Date: 1998-07-09 Impact factor: 91.245