title: Repeated-dose toxicological studies of Tithonia diversifolia (Hemsl.) A. gray and identification of the toxic compounds.
abstract: BACKGROUND
  Tithonia diversifolia (Hemsl.) A. Gray has been commonly used in folk medicine to treat abscesses, microbiological infections, snake bites, malaria and diabetes. Both anti-inflammatory and anti-malarial properties have been identified using appropriate assays, but the effective doses have demonstrated toxic effects for the experimental animals. Most of the pharmacological activities have been attributed to sesquiterpene lactones (STLs) and some chlorogenic acid derivatives (CAs) in the leaves of this species. This work aimed to evaluate the repeated-dose toxicity of an aqueous extract (AE) from Tithonia diversifolia leaves and to compare the results with an extract rich in STLs (LRE) and a polar extract (PE) without STLs but rich in CAs. The purpose of this work was to provide insights into the identity of the compounds responsible for the toxic effects of Tithonia diversifolia.
  
  
  METHODS
  The major classes of compounds were confirmed in each extract by IR spectra and HPLC-UV-DAD profiling using previously isolated or standard compounds. The toxicity of each extract was evaluated in a repeated-dose toxicity study in Wistar rats for 90 days.
  
  
  RESULTS
  The AE is composed of both STLs and CAs, the LRE is rich in STLs, and the PE is rich in CAs. The AE caused alterations in haematological parameters but few alterations in biochemical parameters and was relatively safe at doses lower than 100mg/kg. However, the PE and LRE demonstrated several adverse effects by damaging the liver and kidneys, respectively.
  
  
  CONCLUSIONS
  STLs and CAs can be toxic in prolonged use at higher doses in extracts prepared from Tithonia diversifolia by affecting the kidneys and liver.
authors.affiliation: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP), Universidade de São Paulo (USP), Departamento de Ciências Farmacêuticas. Av. do Café s/no, Ribeirão Preto-SP 14040-903, Brazil.
authors.forename: Flávia Donaire
authors.initials: FD
authors.lastname: Passoni
authors.forename: Rejane Barbosa
authors.initials: RB
authors.lastname: Oliveira
authors.forename: Daniela Aparecida
authors.initials: DA
authors.lastname: Chagas-Paula
authors.forename: Leonardo
authors.initials: L
authors.lastname: Gobbo-Neto
authors.forename: Fernando Batista
authors.initials: FB
authors.lastname: Da Costa
mesh_terms: D000818:Animals; D019659:Asteraceae; D002726:Chlorogenic Acid / Q000031:analogs & derivatives / Q000633:toxicity; D005260:Female; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D007783:Lactones / Q000633:toxicity; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D009929:Organ Size / Q000187:drug effects; D010936:Plant Extracts / Q000633:toxicity*; D018515:Plant Leaves; D051381:Rats; D017208:Rats, Wistar; D012717:Sesquiterpenes / Q000633:toxicity; D013154:Spleen / Q000187:drug effects / Q000473:pathology; D013950:Thymus Gland / Q000187:drug effects / Q000473:pathology; D059550:Toxicity Tests, Subchronic
chemical_list: D007783:Lactones; D010936:Plant Extracts; D012717:Sesquiterpenes; D002726:Chlorogenic Acid