Characteristics of 2,3,7,8-tetrachlorodibenzo-p-dioxin induced endotoxin hypersensitivity: association with hepatotoxicity
| Autor: | Michael I. Luster, Thigpen Je, Ralph E. Wilson, Ann N. Tucker, Gary J. Rosenthal, Edward H. Lebetkin |
|---|---|
| Rok vydání: | 1989 |
| Předmět: |
Blood Glucose
medicine.medical_specialty Polychlorinated Dibenzodioxins Ratón Receptors Drug Congenic Endogeny Inflammation Toxicology Dioxins Methylprednisolone Blood Urea Nitrogen chemistry.chemical_compound Mice Internal medicine medicine Animals heterocyclic compounds Drug Interactions Liver Diseases Alanine Transaminase Lipids Uridine Tetrachlorodibenzo-p-dioxin Endotoxins Mice Inbred C57BL stomatognathic diseases Endocrinology chemistry Receptors Aryl Hydrocarbon Mice Inbred DBA RNA Female Liver dysfunction medicine.symptom Chemical and Drug Induced Liver Injury medicine.drug |
| Zdroj: | Toxicology. 56(3) |
| ISSN: | 0300-483X |
| Popis: | Hepatic clearance is a major route of endotoxin detoxification. In the present study, the potential relationship between TCDD-induced endotoxin hypersensitivity and hepatotoxicity was examined. Acute doses of 50, 100, o 200 μg TCDD/kg body weight induced an endotoxin hypersensitive state in B6C3F 1 mice as demontrated by increased mortality 24–48 h following i.v. injection of endotoxin. This hypersensitive state occurred when endotoxin was administered 7 days following TCDD exposure, but not 1 day post-TCDD exposure. TCDD did not affect endogenous serum endotoxin levels. However, clearance of injected endotoxin was significantly inhibited following exposure to TCDD. Six hours post endotoxin treatment serum triglycerides were significantly increased in TCDD/endotoxin-treated mice compared to either treatment alone. Methylprednisolone and uridine were both examined in this model due to their roles in inflammation and RNA synthesis, respectively. Both compounds significantly reversed the mortality associated with the combined exposure. [ 3 H]Uridine incorporation into liver was decreased following TCDD treatment alone, further suggesting impaired RNA synthesis. Studies performed on congenic mice indicate that the observed effects segregate with the Ah locus. The ability of methylprednisolone and uridine to reverse the mortality associated with TCDD/endotoxin treatment is consistent with an inflammatory response and impaired hepatic detoxification mechanisms. Thus, changes in hepatic handling of endotoxin, caused by progressive TCDD-induced liver dysfunction, may be responsible for the endotoxin hypersensitivity. |
| Databáze: | OpenAIRE |
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