Dialkylquinonimines validated as in vivo metabolites of alachlor, acetochlor, and metolachlor herbicides in rats

Chemical Research in Toxicology
P R JefferiesJ E Casida

Abstract

The oncogenicity of chloroacetanilide herbicides (1-5) is proposed to involve bioactivation to 2,6-dialkylbenzoquinonimines (quinonimines, 9) based on two earlier observations: (1) in vitro conversion of the alachlor (1) metabolite diethylaniline (7Et2) to 2, 6-diethylquinonimine (9Et2) which reacts readily with GSH and (2) induction of sister chromatid exchanges in human lymphocytes for the parent herbicides and their purported 9 metabolites. This hypothesis lacks in vivo evidence for 9 formation which might be provided by analysis of urine and tissue for thiol adducts of 9. Accordingly, two mercapturates (10Et2 and 10Me2) and a cysteine conjugate (11Me2) were prepared by addition of N-acetylcysteine or cysteine to 9Et2 and the 2,6-dimethyl homologue (9Me2). Mercapturate 10Et2 was characterized by HPLC using the urine of rats treated ip with hydroxyaniline 8Et2, and both mercapturate 10Me2 and cysteine conjugate 11Me2 were found in the urine of mice administered hydroxyaniline 8Me2. The mercapturates were then converted to the N, N-dimethyl-2,6-dialkyl-4-methoxy-3-(methylthio)anilines (12Et2, 12EtMe, and 12Me2) by alkaline permethylation, thereby providing a method for analysis of 9-derived thiol adducts in urine and liver as ...Continue Reading

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Citations

Dec 21, 2006·Toxicologic Pathology·Alan M JeffreyGary M Williams
Jul 27, 2012·Toxicological Sciences : an Official Journal of the Society of Toxicology·Ming-Wei ChaoGerald N Wogan
Nov 24, 2004·Drug Metabolism Reviews·Ulrich Hoffmann, Heyo K Kroemer
Feb 13, 2016·ACS Chemical Biology·Kodihalli C RavindraPaul L Skipper
Feb 22, 2012·Regulatory Toxicology and Pharmacology : RTP·Vincent J PiccirilloW James Bover
Apr 23, 2005·Toxicology and Applied Pharmacology·Elaine M LeslieSusan P C Cole
Jul 12, 2014·Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association·Pinar ErkekogluSteven R Tannenbaum
May 19, 2016·Journal of Agricultural and Food Chemistry·John E Casida
Feb 15, 2008·Journal of Biochemical and Molecular Toxicology·Vijay M KaleSharon A Meyer

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