title: Glutathione-dependent cytotoxicity of the chloroacetanilide herbicides alachlor, metolachlor, and propachlor in rat and human hepatoma-derived cultured cells.
abstract: Alachlor, metolachlor, and propachlor are widely used chloroacetanilide herbicides. Their cytotoxicity in rat (Fa32) and human (Hep G2) hepatoma-derived cells was investigated, in connection with their influence on the endogenous glutathione (GSH) content, on the xenobiotic-metabolizing phase I enzymes 7-ethoxyresorufin O-deethylase (EROD) and 7-pentoxyresorufin O-depentylase (PROD), and phase II glutathione transferase (GST). The cytotoxicity was measured by the neutral red uptake inhibition assay. The following toxicity range was observed in both cell lines: propachlor > alachlor > metolachlor. When the endogenous GSH content was reduced by pretreatment of the cells with L-buthionine (S,R)-sulfoximine, the cytotoxicity of the herbicides increased strongly in both cell lines. EROD and PROD activities were dose-dependently increased to different degrees in Fa32, as was EROD in Hep G2, but no PROD activity was observed in these cells. The GSH content was not altered after 1 h treatment, and was approximately doubled after 24 h. GST activity was increased in Fa32 cells but not in Hep G2. A comparable cytotoxicity was observed for the investigated chloroacetanilides in both the rat and the human cell lines. Different interactions with xenobiotic-metabolizing phase I and II enzymes were observed, and GSH showed a protective effect against the acetanilides in both cell lines.
authors.affiliation: Instituut voor Volksgezondheid, Afdeling Toxikologie, Brussels, Belgium. p.dierickx@iph.fgov.be
authors.forename: P J
authors.initials: PJ
authors.lastname: Dierickx
mesh_terms: D000081:Acetamides / Q000633:toxicity*; D000083:Acetanilides / Q000633:toxicity; D000818:Animals; D006528:Carcinoma, Hepatocellular; D004396:Coloring Agents / Q000493:pharmacokinetics; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D019362:Cytochrome P-450 CYP2B1 / Q000378:metabolism; D003603:Cytotoxins / Q000633:toxicity; D005326:Fetal Proteins / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism*; D005982:Glutathione Transferase / Q000378:metabolism; D006540:Herbicides / Q000633:toxicity*; D006801:Humans; D009499:Neutral Red / Q000493:pharmacokinetics; D051381:Rats; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000201:enzymology
chemical_list: D000081:Acetamides; D000083:Acetanilides; D004396:Coloring Agents; D003603:Cytotoxins; D005326:Fetal Proteins; D006540:Herbicides; C011088:propachlor; C000188:alachlor; D009499:Neutral Red; D019363:Cytochrome P-450 CYP1A1; D019362:Cytochrome P-450 CYP2B1; D005982:Glutathione Transferase; D005978:Glutathione; C051786:metolachlor