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IMPROVING STRUCTURE-LINKED ACCESS TO PUBLICLY AVAILABLE CHEMICAL TOXICITY INFORMATION
Citation:
Richard, A. M., C. R. Williams, AND N. F. Carrielo. IMPROVING STRUCTURE-LINKED ACCESS TO PUBLICLY AVAILABLE CHEMICAL TOXICITY INFORMATION. CURRENT OPINION IN DRUG DISCOVERY & DEVELOPMENT 5(1):136-143, (2001).
Description:
Hepatotoxicity of the Herbicide Alachlor Associated with Glutathione Depletion, Oxidative Damage and Protein S-Cysteinyl Adduction.
Toxicity of the herbicide alachlor (2-chloro-2',6'-diethtl-N-[methoxtmethtl]-acetanilide) has been attributed to cytochrome P450-dependent metabolism to prooxidant quinoneimine (QI). These studies addressed the role of QI in alachlor hepatotoxicity by examining histological patterns of liver injury, depletion of glutathione (GSH, as non-protein sulfhydryls), formation of thiobarbituric acid-reactive products of lipid peroxidation (TBARS), and levels of oxidant-induced glutathione S-transferase (GST) activity and immunologically determined isozyme protein. Serum sorbitol dehydrogenase and hepatic TBARS and GST activity of male Long-Evans rats treated with alachlor (126-600 mg/kg, ip) exhibited dose-dependent increases reaching significance 24 h after >400 mg/kg. Time-dependent increases in TBARS and GST-a and - isoforms occurred with daily administrations of a subtoxic dose (126 mg/kg) over 1, 4 and 28 days. Shortly after a subtoxic dose (2-4 h, 126 mg/kg), GSH dropped by -50%, then recovered by 24 h. GSH remained depressed by 40-45% 24 h after toxic doses of alachlor or acetaminophen (APAP, 900 mg/kg, ip), another cytochrome P450-dependent QI precursor. Although these biochemical results supported mechanistic similarities, alachlor produced hepatocellular necrosis through the midlobular region distinct from APAP-induced centrilobular degeneration. Alachlor S-cysteintl protein adducts in livers of treated rats were readily detectable by GC-MS from their characteristic product [3-(2',6'-diethylphenyl)-1,3-thiazolidine-4-one] with methanesulfonic acid, suggesting that nucleophilic substitution of chloroacettl chlorine of alachlor significantly contributed to GSH depletion. Collectively, these data indicate that GSH depletion resulting from conjugation of the parent molecule, in addition to that consumed by detoxication of the QI metabolite and secondary reactive oxidants, elicits oxidative damage that mediates alachlor hepatotoxicity.
Disclaimer: The research described in this article has been reviewed by the National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency and approved for publication. Approval does not signify that the contents necessarily reflect the views of the Agency nor does mention of trade names or commercial products constitute endorsement or recommendation for use.