Induction of hepatic metallothionein by paraquat
| Autor: | Cherukury Madhu, Yaping Liu, Curtis D. Klaassen, John W. Bauman, James M. McKim |
|---|---|
| Rok vydání: | 1992 |
| Předmět: |
Male
Paraquat inorganic chemicals medicine.medical_specialty Time Factors Molecular Sequence Data Toxicology medicine.disease_cause Mice chemistry.chemical_compound Internal medicine medicine Animals Bile Metallothionein heterocyclic compounds RNA Messenger Cells Cultured Pharmacology chemistry.chemical_classification Reactive oxygen species Base Sequence Dose-Response Relationship Drug Glutathione Disulfide Glutathione Zinc Endocrinology Liver Mechanism of action chemistry Biochemistry Toxicity Potassium Glutathione disulfide medicine.symptom Oxidative stress |
| Zdroj: | Toxicology and Applied Pharmacology. 117:233-241 |
| ISSN: | 0041-008X |
| Popis: | Paraquat, a frequently used contact herbicide, produces oxidative stress by undergoing redox cycling and generating reactive oxygen species. Paraquat is also effective at increasing hepatic levels of metallothionein (MT). The mechanism(s) by which agents that induce oxidative stress produce increases in MT concentrations is not yet known. Therefore, the goal of the current study was to characterize the elevation in hepatic MT produced by paraquat administration to mice and to examine potential mechanism(s) of this increase. A dose-response study for increases in MT showed that administration of 0.1 to 0.5 mmol/kg of paraquat, sc, increased hepatic MT with a maximal increase of 36-fold. Subsequent studies were carried out with paraquat at a dose (0.3 mmol/kg, sc) that caused oxidative stress, as shown by a 35-fold increase in the biliary excretion of oxidized glutathione. There were coordinate elevations of both hepatic MT-I and MT-II mRNA of approximately 5-fold with peaks at both 6 and 24 hr after paraquat. The time course for the elevation in hepatic MT protein following paraquat treatment showed that MT levels had a maximal increase of 18-fold obtained at 36 hr. Paraquat appears to be an indirect MT inducer, in that there were no elevations in MT when cultured mouse hepatocytes were exposed to paraquat. No rise in liver Zn was observed prior to the increase in hepatic MT, thus, a Zn redistribution to the liver did not cause the increase in hepatic MT following paraquat administration. Adrenalectomy did not abolish the increase in MT produced by paraquat, suggesting that adrenal gland products are not required for the increase in MT produced by paraquat. In conclusion, the chemical mediator responsible for the increase in hepatic MT after paraquat was not determined, but the elevation in MT concentration appears to be due to increased transcription. |
| Databáze: | OpenAIRE |
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