RESUMEN
TCDD-inducible poly-ADP-ribose polymerase (TIPARP) is an aryl hydrocarbon receptor (AHR) target gene that functions as part of a negative feedback loop to repress AHR activity. Tiparp-/- mice exhibit increased sensitivity to the toxicological effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), including lethal wasting syndrome. However, it is not known whether Tiparp-/- mice also exhibit increased sensitivity to other AHR ligands. In this study, we treated male Tiparp-/- or wild type (WT) mice with a single injection of 100 mg/kg 3-methylcholanthrene (3MC). Consistent with TIPARP's role as a repressor of AHR signaling, 3MC-treated Tiparp-/- mice exhibited increased hepatic Cyp1a1 and Cyp1b1 levels compared with WT mice. No 3MC-treated Tiparp-/- mice survived beyond day 16 and the mice exhibited chylous ascites characterized by an accumulation of fluid in the peritoneal cavity. All WT mice survived the 30-day treatment and showed no signs of fluid accumulation. Treated Tiparp-/- mice also exhibited a transient and mild hepatotoxicity with inflammation. 3MC-treated WT, but not Tiparp-/- mice, developed mild hepatic steatosis. Lipid deposits accumulated on the surface of the liver and other abdominal organs in the 3MC-Tiparp-/- mice. Our study reveals that Tiparp-/- mice have increased sensitivity to 3MC-induced liver toxicity, but unlike with TCDD, lethality is due to chylous ascites rather than wasting syndrome.
Asunto(s)
Ascitis Quilosa/inducido químicamente , Ascitis Quilosa/enzimología , Metilcolantreno/toxicidad , Poli(ADP-Ribosa) Polimerasas/metabolismo , Dibenzodioxinas Policloradas/toxicidad , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/patología , Animales , Compuestos Azo/farmacología , Ascitis Quilosa/patología , Citocinas/metabolismo , Hígado Graso/enzimología , Hígado Graso/patología , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Inflamación/patología , Mediadores de Inflamación/metabolismo , Hígado/efectos de los fármacos , Hígado/enzimología , Hígado/patología , Masculino , Ratones Noqueados , Poli(ADP-Ribosa) Polimerasas/genética , Pirazoles/farmacología , Receptores de Hidrocarburo de Aril/metabolismo , Transducción de Señal , Análisis de SupervivenciaAsunto(s)
Adenocarcinoma del Pulmón/complicaciones , Adenocarcinoma del Pulmón/genética , Ascitis Quilosa/etiología , Neoplasias Pulmonares/complicaciones , Neoplasias Pulmonares/genética , Adenocarcinoma del Pulmón/enzimología , Adenocarcinoma del Pulmón/patología , Anciano , Ascitis Quilosa/enzimología , Ascitis Quilosa/genética , Ascitis Quilosa/patología , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/enzimología , Neoplasias Pulmonares/patología , Masculino , MutaciónRESUMEN
The long-term effects of chain length of dietary fat on intestinal lymphatic transport of alkaline phosphatase were investigated in two patients with chylous ascites due to leakage of intestinal lymph into the peritoneal cavity. Substitution of a medium-chain triglyceride diet for long-chain triglyceride resulted in a parallel fall in triglyceride and the intestinal isoenzyme of alkaline phosphatase in chylous ascites. The concentrations of lymph triglyceride were linearly related to lymph intestinal alkaline phosphatase levels, suggesting a positive relation between absorption of long-chain triglycerides and transport of mucosal alkaline phosphatase into lymph.