Thiram (tetramethylthiurum disulfide) is widely used as a fungicide to protect pre- and post-harvested crops from fungal disease. It is also used in medicine an antibacterial agent and in rubber/rayon industry as an antioxidant. Thus, there is a high potential for human exposure to this pesticide. Exposure to thiram results in various toxic effects including impairment of hematopoiesis, fertility and nervous system, thyroid dysfunction, and degeneration of liver. Its interaction with alcohol, drugs, metals and nitrite can be dangerous. It is metabolized in the body to dimethyldithiocarbamate (DMDC) and carbon disulfide (CS2), which cause hepatotoxicity. The proposed studies will investigate the hypothesis that thiram and its two metabolites inhibit hepatic cytochrome P450 (CYP) isoforms 1A1, 3A4, 2B1 and 2E1, and this effect is responsible for hepatic damage. Thus, the inhibitory effect of these toxicants on the constitutive and inducible CYP isoforms will be studied first in whole animals and then with liver microsomes, and the relationship between the CYP inhibition and hepatotoxicity will be explored. To achieve this goal, first, thiram, DMDC and CS2 will be administered to rats and their effect on liver constitutive and inducible CYP isozymes 1A1, 3A4, 2B1 and 2E1 will be determined using specific substrates of the isozymes. The relationship between the inhibition of CYP isoforms and hepatic damage will be determined using serum enzyme tests and histopathological examination of the livers. In vitro assays with liver microsomes and the inhibitory compounds will be conducted to ascertain/identify which CYP isoforms is/are affected the most. Thus, the overall aim of these studies is to define the role of CYP isozymes in the metabolism of thiram and its two toxic metabolites DMDC and CS2, and identify the CYP isozymes most involved in the hepatic damages associated with the exposure to these toxic chemicals.
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