title: Elements of margin of safety, toxicity and action of sodium selenite in a lipopolysaccharide rat model.
abstract: METHODS
  Both septic shock and sodium selenite (Na2SeO3) lead to multiple organ failure through oxidation. Na2SeO3 has direct oxidant effects above the nutritional level and indirect anti-oxidant properties. In a lipopolysaccharide (LPS) rat model we assessed margin of safety, toxicity and beneficial effect of pentahydrate Na2SeO3 (5H2O·Na2SeO3) at oxidant doses.
  
  
  METHODS
  In a three-step study on 204 rats we: (i) observed toxic effects of Na2SeO3 injected intraperitoneously (IP) and determined its Minimum Dose Without Toxic effect (MDWT) 0.25-0.35 mg/kg selenium (Se) content; (ii) injected IP LPS at 70% lethal dose (LD) followed, or not, one hour later by IP Na2SeO3 at MDWT and (iii) by doses>MDWT. At 48 h, in survivors, we measured plasma creatinine, lactate, aspartate and alanine aminotransferase (AST, ALT), nitric oxide (NO) and Se concentrations.
  
  
  RESULTS
  (i) Na2SeO3 alone did not increase NO and lactate. Encephalopathy appeared at 1mg Se/kg. Creatinine increased at 1-1.75 mg Se/kg, AST, ALT at 3-4.5 mg Se/kg, and the minimum LD was 3 mg Se/kg. (ii) Mortality after LPS was 37/50 (74%, [62-86%]) vs. 20/30 (67%, [50-84%]) when followed by Na2SeO3 at MDWT (p=0.483) with a decreased in NO (-31%, p=0.038) a trend for lactate decrease (-19%, p=0.068) and an increased Se in plasma of survivals. (iii) All rats died at doses ≥0.6 mg/kg (p<0.001).
  
  
  CONCLUSIONS
  Mechanisms of LPS and Na2SeO3 toxicity differ (i.e. NO, lactate). In septic shock 5H2O·Na2SeO3 toxicity increased, margin of safety decrease, but IP administration of dose considered as oxidant of 5H2O·Na2SeO3 showed beneficial effects.
authors.affiliation: Centre Hospitalier de Meaux, Réanimation Polyvalente, 77104 Meaux, France. Electronic address: xforceville@invivo.edu.
authors.forename: Xavier
authors.initials: X
authors.lastname: Forceville
authors.affiliation: Centre Hospitalier de Meaux, Réanimation Polyvalente, 77104 Meaux, France.
authors.forename: Samia
authors.initials: S
authors.lastname: Touati
authors.affiliation: Hôpital Avicenne, 125 Route de Stalingrad, 93009 Bobigny, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Le Toumelin
authors.affiliation: CHU de Grenoble, Département de Biochimie Toxicologie & Pharmacologie, UF de Biochimie Hormonologie & Nutrition, BP 217, 38043 Grenoble cedex 9, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Ducros
authors.affiliation: CHU de Grenoble, Département de Biochimie Toxicologie & Pharmacologie, UF de Biochimie Hormonologie & Nutrition, BP 217, 38043 Grenoble cedex 9, France.
authors.forename: François
authors.initials: F
authors.lastname: Laporte
authors.affiliation: Institut de Recherche Biomédicale des Armées, Département des Effets Biologiques des Rayonnements, 24 avenue des Maquis du Grésivaudan - BP 87, 38702 La Tronche, France.
authors.forename: Yves
authors.initials: Y
authors.lastname: Chancerelle
authors.affiliation: Institut de Recherche Biomédicale des Armées, Département des Effets Biologiques des Rayonnements, 24 avenue des Maquis du Grésivaudan - BP 87, 38702 La Tronche, France.
authors.forename: Diane
authors.initials: D
authors.lastname: Agay
mesh_terms: D000818:Animals; D008297:Male; D009102:Multiple Organ Failure / Q000139:chemically induced*; D051381:Rats; D012643:Selenium / Q000494:pharmacology; D018038:Sodium Selenite / Q000494:pharmacology*
chemical_list: D012643:Selenium; D018038:Sodium Selenite
keywords: Drug; Multiple organ failure; Oxidation; Selenium; Septic shock