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A new and vital antidotal pathway for paraquat poisonings more than 60 years later: Induction of lung P-glycoprotein
Abstracts / Toxicology Letters 164S (2006) S1–S324
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directly associated with the PMN. The incidence of these pathomorphological findings increased from 20% after 3 months of exposure to 80% after 12 months of exposure in both diets. Interstitial lymphocytic infiltrates were present in 80% of these mice only after 12 months of exposure. The pathomorphological alterations were not influenced by high-fat diet. In summary, our data indicate that chronic exposure of ApoE−/− mice to 200 g TPM/l MS results in non-neoplastic pathomorphological changes in the lung and an inflammatory response, which is a mixture of innate and adaptive immune responses, as indicated by an increase in BALF neutrophils and lymphocytes.
tion to about 40% of the only PQ-exposed group, and led to an improvement of tissue healing in just 24 h as a result of the induction of de novo synthesis of P-glycoprotein (P-gp). The involvement of P-gp in these effects was confirmed by Western blot analysis and by the use of verapamil (10 mg/kg i.p.), a competitive inhibitor of this transporter, which given one hour before dexamethasone blocked its protective effects, causing instead an increase of PQ lung concentration and an aggravation of toxicity. In conclusion, the induction of P-gp, leading to a decrease in lung levels of PQ and the consequent prevention of toxicity, seems to be a new and promising treatment of PQ poisonings.
doi:10.1016/j.toxlet.2006.06.155
Ricardo Dinis-Oliveira, acknowledges FCT for his Ph.D. grant (SFRH/BD/13707/2003).
P2-15 A new and vital antidotal pathway for paraquat poisonings more than 60 years later: Induction of lung P-glycoprotein Ricardo Jorge Dinis-Oliveira 1,3 , Fernando Remi˜ao 1,3 , Jos´e Alberto Duarte 2 , Rita Ferreira 2 , Amparo S´anchez Navarro 3 , Maria de Lourdes Bastos 1,3 , F´elix Carvalho 1,3 1 REQUIMTE,
Department of Toxicology, Faculty of Pharmacy, University of Porto, Rua An´ıbal Cunha, 164, 4099-030 Porto, Portugal; 2 Department of Sport Biology, Faculty of Sport Sciences, University of Porto, Rua Dr. Pl´acido Costa, 91, 4200-450 Porto, Portugal; 3 Faculty of Pharmacy, Avenida Campo Charro s/n, 37007 Salamanca, Spain The widespread use of the non-selective contact herbicide paraquat (PQ) has been the cause of thousands of deaths from both accidental and voluntary ingestion. The main target organ for PQ toxicity of is the lung. This is mainly due to a characteristic polyamine uptake system in this organ for which PQ is a preferential substrate. Due to the lack of antidotes for PQ poisoning, the prognosis has been primarily based on the plasma and urine concentration of PQ within the first 24 h of intoxication. No antidote or effective treatment was developed until now to decrease the PQ accumulation in the lung or to disrupt its toxicity. In the present study, a procedure that conducts to a remarkable decrease of PQ accumulation in the lung, together with an increase of faecal excretion and a subsequent decrease of several biochemical and histopathological biomarkers of toxicity, is described. The administration of dexamethasone (100 mg/kg i.p.) to Wistar rats, two hours after PQ intoxication (25 mg/kg i.p.), decreased the PQ lung accumula-
doi:10.1016/j.toxlet.2006.06.156 P2-16 Drug pharmacokinetic in hepatodysfunction: A possible way to toxicity Berta S˜ao Braz, Ana L. Rodrigues, Adriana Belas, A. Jorge Silva Faculty of Veterinary Medicine/CIISA, Lisboa, Portugal When a medicine marketing authorization is asked to Competent Authorities, a therapeutic scheme must be established and proposed. Pharmacokinetic studies needed to achieve that goal are performed in healthy animal not taking in account potential interferences of disease states. Hepatic diseases and subsequent hepatic dysfunction must be responsible by a modified hepatic metabolizing activity, which can modulate pharmacokinetics with influence in drug therapeutic activity and toxicity. This study was delineated in order to determine influence of hepatic dysfunction on pharmacokinetic of antipyrine (AP), a low-clearance compound, and hexobarbital (HB) an intermediate high-clearance compound. Hepatic dysfunction was induced by intraperitoneal administration (IP) of galactosamine (hepatotoxin used as acute hepatitis model) to Wistar male rats. AP (50 mg/kg, IP) and HB (100 mg/kg, gavage) were administered to animals 24, 48 and 72 h after hepatotoxicity induction, after what blood samples were collected. Antipyrine analytical determination in plasma samples was performed by enzymatic hydrolysis (with Limpet Acetone Powder), extraction (chloroform/ethanol mixture (9/1, v/v)), evaporation to dryness and dilution (phosphate buffer and methanol) before injection onto HPLC column (Nova Pack C18 column Waters), with
S75
directly associated with the PMN. The incidence of these pathomorphological findings increased from 20% after 3 months of exposure to 80% after 12 months of exposure in both diets. Interstitial lymphocytic infiltrates were present in 80% of these mice only after 12 months of exposure. The pathomorphological alterations were not influenced by high-fat diet. In summary, our data indicate that chronic exposure of ApoE−/− mice to 200 g TPM/l MS results in non-neoplastic pathomorphological changes in the lung and an inflammatory response, which is a mixture of innate and adaptive immune responses, as indicated by an increase in BALF neutrophils and lymphocytes.
tion to about 40% of the only PQ-exposed group, and led to an improvement of tissue healing in just 24 h as a result of the induction of de novo synthesis of P-glycoprotein (P-gp). The involvement of P-gp in these effects was confirmed by Western blot analysis and by the use of verapamil (10 mg/kg i.p.), a competitive inhibitor of this transporter, which given one hour before dexamethasone blocked its protective effects, causing instead an increase of PQ lung concentration and an aggravation of toxicity. In conclusion, the induction of P-gp, leading to a decrease in lung levels of PQ and the consequent prevention of toxicity, seems to be a new and promising treatment of PQ poisonings.
doi:10.1016/j.toxlet.2006.06.155
Ricardo Dinis-Oliveira, acknowledges FCT for his Ph.D. grant (SFRH/BD/13707/2003).
P2-15 A new and vital antidotal pathway for paraquat poisonings more than 60 years later: Induction of lung P-glycoprotein Ricardo Jorge Dinis-Oliveira 1,3 , Fernando Remi˜ao 1,3 , Jos´e Alberto Duarte 2 , Rita Ferreira 2 , Amparo S´anchez Navarro 3 , Maria de Lourdes Bastos 1,3 , F´elix Carvalho 1,3 1 REQUIMTE,
Department of Toxicology, Faculty of Pharmacy, University of Porto, Rua An´ıbal Cunha, 164, 4099-030 Porto, Portugal; 2 Department of Sport Biology, Faculty of Sport Sciences, University of Porto, Rua Dr. Pl´acido Costa, 91, 4200-450 Porto, Portugal; 3 Faculty of Pharmacy, Avenida Campo Charro s/n, 37007 Salamanca, Spain The widespread use of the non-selective contact herbicide paraquat (PQ) has been the cause of thousands of deaths from both accidental and voluntary ingestion. The main target organ for PQ toxicity of is the lung. This is mainly due to a characteristic polyamine uptake system in this organ for which PQ is a preferential substrate. Due to the lack of antidotes for PQ poisoning, the prognosis has been primarily based on the plasma and urine concentration of PQ within the first 24 h of intoxication. No antidote or effective treatment was developed until now to decrease the PQ accumulation in the lung or to disrupt its toxicity. In the present study, a procedure that conducts to a remarkable decrease of PQ accumulation in the lung, together with an increase of faecal excretion and a subsequent decrease of several biochemical and histopathological biomarkers of toxicity, is described. The administration of dexamethasone (100 mg/kg i.p.) to Wistar rats, two hours after PQ intoxication (25 mg/kg i.p.), decreased the PQ lung accumula-
doi:10.1016/j.toxlet.2006.06.156 P2-16 Drug pharmacokinetic in hepatodysfunction: A possible way to toxicity Berta S˜ao Braz, Ana L. Rodrigues, Adriana Belas, A. Jorge Silva Faculty of Veterinary Medicine/CIISA, Lisboa, Portugal When a medicine marketing authorization is asked to Competent Authorities, a therapeutic scheme must be established and proposed. Pharmacokinetic studies needed to achieve that goal are performed in healthy animal not taking in account potential interferences of disease states. Hepatic diseases and subsequent hepatic dysfunction must be responsible by a modified hepatic metabolizing activity, which can modulate pharmacokinetics with influence in drug therapeutic activity and toxicity. This study was delineated in order to determine influence of hepatic dysfunction on pharmacokinetic of antipyrine (AP), a low-clearance compound, and hexobarbital (HB) an intermediate high-clearance compound. Hepatic dysfunction was induced by intraperitoneal administration (IP) of galactosamine (hepatotoxin used as acute hepatitis model) to Wistar male rats. AP (50 mg/kg, IP) and HB (100 mg/kg, gavage) were administered to animals 24, 48 and 72 h after hepatotoxicity induction, after what blood samples were collected. Antipyrine analytical determination in plasma samples was performed by enzymatic hydrolysis (with Limpet Acetone Powder), extraction (chloroform/ethanol mixture (9/1, v/v)), evaporation to dryness and dilution (phosphate buffer and methanol) before injection onto HPLC column (Nova Pack C18 column Waters), with