title: A study of toxicity and differential gene expression in murine liver following exposure to anti-malarial drugs: amodiaquine and sulphadoxine-pyrimethamine.
abstract: BACKGROUND
  Amodiaquine (AQ) along with sulphadoxine-pyrimethamine (SP) offers effective and cheaper treatment against chloroquine-resistant falciparum malaria in many parts of sub-Saharan Africa. Considering the previous history of hepatitis, agranulocytosis and neutrocytopenia associated with AQ monotherapy, it becomes imperative to study the toxicity of co-administration of AQ and SP. In this study, toxicity and resulting global differential gene expression was analyzed following exposure to these drugs in experimental Swiss mice.
  
  
  METHODS
  The conventional markers of toxicity in serum, oxidative stress parameters in tissue homogenates, histology of liver and alterations in global transcriptomic expression were evaluated to study the toxic effects of AQ and SP in isolation and in combination.
  
  
  RESULTS
  The combination therapy of AQ and SP results in more pronounced hepatotoxicity as revealed by elevated level of serum ALT, AST with respect to their individual drug exposure regimen. Furthermore, alterations in the activity of major antioxidant enzymes (glutathione peroxidase, superoxide dismutase, catalase, glutathione reductase), indicating the development of oxidative stress, was more significant in AQ+SP combination therapy. cDNA microarray results too showed considerably more perturbed gene expression following combination therapy of AQ and SP as compared to their individual drug treatment. Moreover, a set of genes were identified whose expression pattern can be further investigated for identifying a good biomarker for potential anti-malarial hepatotoxicity.
  
  
  CONCLUSIONS
  These observations clearly indicate AQ+SP combination therapy is hepatotoxic in experimental Swiss mice. Microarray results provide a considerable number of potential biomarkers of anti-malarial drug toxicity. These findings hence will be useful for future drug toxicity studies, albeit implications of this study in clinical conditions need to be monitored with cautions.
authors.affiliation: Genotoxicity Laboratory, Toxicology Division, Central Drug Research Institute, CSIR, Lucknow, PIN 226 001, India.
authors.forename: Shrawan Kumar
authors.initials: SK
authors.lastname: Mishra
authors.forename: Prabhat
authors.initials: P
authors.lastname: Singh
authors.forename: Srikanta Kumar
authors.initials: SK
authors.lastname: Rath
mesh_terms: D000655:Amodiaquine / Q000008:administration & dosage / Q000009:adverse effects*; D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage / Q000009:adverse effects*; D004338:Drug Combinations; D004359:Drug Therapy, Combination / Q000379:methods; D020869:Gene Expression Profiling; D006651:Histocytochemistry; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008297:Male; D051379:Mice; D046228:Microarray Analysis; D018384:Oxidative Stress; D011739:Pyrimethamine / Q000008:administration & dosage / Q000009:adverse effects*; D013413:Sulfadoxine / Q000008:administration & dosage / Q000009:adverse effects*
chemical_list: D000962:Antimalarials; D004338:Drug Combinations; D000655:Amodiaquine; C001205:fanasil, pyrimethamine drug combination; D013413:Sulfadoxine; D011739:Pyrimethamine