title: In vitro metabolism of methiocarb and carbaryl in rats, and its effect on their estrogenic and antiandrogenic activities.
abstract: In this work, we examined the metabolism of the carbamate insecticides methiocarb and carbaryl by rat liver microsomes and plasma, and its effect on their endocrine-disrupting activities. Methiocarb and carbaryl were not enzymatically hydrolyzed by rat liver microsomes, but were hydrolyzed by rat plasma, mainly to methylthio-3,5-xylenol (MX) and 1-naphthol, respectively. When methiocarb was incubated with rat liver microsomes in the presence of NADPH, methiocarb sulfoxide was formed. The hydrolysis product, MX, was also oxidized to the sulfoxide, 3,5-dimethyl-4-(methylsulfinyl)phenol (SP), by rat liver microsomes in the presence of NADPH. These oxidase activities were catalyzed by cytochrome P450 and flavin-containing monooxygenase. Methiocarb and carbaryl both exhibited estrogen receptor α (ERα) and ERβ agonistic activity. MX and 1-naphthol showed similar activities, but methiocarb sulfoxide and SP showed markedly decreased activities. On the other hand, methiocarb and carbaryl exhibited potent antiandrogenic activity in the concentration range of 1×10(-6)-3×10(-5) M. Their hydrolysis products, MX, and 1-naphthol also showed high activity, equivalent to that of flutamide. However, methiocarb sulfoxide and SP showed relatively low activity. Thus, hydrolysis of methiocarb and carbaryl and oxidation of methiocarb to the sulfoxide markedly modified the estrogenic and antiandrogenic activities of methiocarb and carbaryl.
authors.affiliation: Graduate School of Biomedical and Health Sciences, Hiroshima University, Kasumi 1-2-3, Minami-ku, Hiroshima 734-8553, Japan.
authors.forename: Satoko
authors.initials: S
authors.lastname: Tange
authors.affiliation: Research Institute for Radiation Biology and Medicine, Hiroshima University, Kasumi 1-2-3, Minami-ku, Hiroshima 734-8553, Japan.
authors.forename: Nariaki
authors.initials: N
authors.lastname: Fujimoto
authors.affiliation: Nihon Pharmaceutical University, Komuro 10281, Ina-machi, Kitaadachi-gun, Saitama 362-0806, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Uramaru
authors.affiliation: School of Pharmacy, China Medical University, No. 91, Hsueh-Shih Rd., Taichung, Taiwan.
authors.forename: Fung Fuh
authors.initials: FF
authors.lastname: Wong
authors.affiliation: Faculty of Pharmaceutical Science, Hiroshima International University, Hirokoshingai 5-1-1, Kure, Hiroshima Prefecture, 737-0112, Japan.
authors.forename: Kazumi
authors.initials: K
authors.lastname: Sugihara
authors.affiliation: Graduate School of Biomedical and Health Sciences, Hiroshima University, Kasumi 1-2-3, Minami-ku, Hiroshima 734-8553, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Ohta
authors.affiliation: Nihon Pharmaceutical University, Komuro 10281, Ina-machi, Kitaadachi-gun, Saitama 362-0806, Japan. Electronic address: kitamura@nichiyaku.ac.jp.
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Kitamura
mesh_terms: D000726:Androgen Antagonists / Q000493:pharmacokinetics*; D000818:Animals; D016466:CHO Cells; D012721:Carbaryl / Q000493:pharmacokinetics*; D002460:Cell Line; D003412:Cricetulus; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004967:Estrogens / Q000493:pharmacokinetics*; D006801:Humans; D006868:Hydrolysis; D066298:In Vitro Techniques; D008099:Liver / Q000502:physiology*; D061986:MCF-7 Cells; D008714:Methiocarb / Q000493:pharmacokinetics*; D009249:NADP / Q000378:metabolism; D010105:Oxygenases / Q000378:metabolism; D010949:Plasma / Q000502:physiology*; D051381:Rats
chemical_list: D000726:Androgen Antagonists; D004967:Estrogens; D009249:NADP; D003577:Cytochrome P-450 Enzyme System; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming); D008714:Methiocarb; D012721:Carbaryl
keywords: Antiandrogenic activity; Carbaryl; Estrogenic activity; Liver microsomes; Methiocarb; Methiocarb sulfoxide; Plasma