title: Enantioselective Metabolism and Interference on Tryptophan Metabolism of Myclobutanil in Rat Hepatocytes.
abstract: Myclobutanil, (RS)-2-(4-chlorophenyl)-2-(1H-1, 2, 4-triazol-1-ylmethyl) hexanenitrile is a widely used triazole fungicide. In this study, enantioselective metabolism and cytotoxicity were investigated in rat hepatocytes by chiral HPLC-MS/MS and the methyl tetrazolium (MTT) assay, respectively. Furthermore, tryptophan metabolism disturbance in rat hepatocytes after myclobutanil exposure was also evaluated by target metabolomics method. The half-life (t1/2) of (+)-myclobutanil was 10.66 h, whereas that for (-)-myclobutanil was 15.07 h. Such results indicated that the metabolic process of myclobutanil in rat hepatocytes was enantioselective with an enrichment of (-)-myclobutanil. For the cytotoxicity research, the calculated EC50 (12 h) values for rac-myclobutanil, (+)- and (-)-myclobutanil were 123.65, 150.65 and 152.60 µM, respectively. The results of tryptophan metabolites profiling showed that the levels of kynurenine (KYN) and XA were both up-regulated compared to the control, suggesting the activation effect of the KYN pathway by myclobutanil and its enantiomers which may provide an important insight into its toxicity mechanism. The data presented here could be useful for the environmental hazard assessment of myclobutanil.
authors.affiliation: Department of Applied Chemistry, China Agricultural University, Beijing, PR China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Institute of Quality Standards & Testing Technology for Agro-Products, Key Laboratory of Agro-Product Quality and Safety, Chinese Academy of Agricultural Sciences, Beijing, PR China.
authors.forename: Jing
authors.initials: J
authors.lastname: Qiu
authors.affiliation: Department of Applied Chemistry, China Agricultural University, Beijing, PR China.
authors.forename: Wentao
authors.initials: W
authors.lastname: Zhu
authors.affiliation: Department of Applied Chemistry, China Agricultural University, Beijing, PR China.
authors.forename: Xinru
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Applied Chemistry, China Agricultural University, Beijing, PR China.
authors.forename: Ping
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Department of Applied Chemistry, China Agricultural University, Beijing, PR China.
authors.forename: Dezhen
authors.initials: D
authors.lastname: Wang
authors.affiliation: Department of Applied Chemistry, China Agricultural University, Beijing, PR China.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Zhou
mesh_terms: D000818:Animals; D003603:Cytotoxins / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity*; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D009570:Nitriles / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D014230:Triazoles / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity*; D014364:Tryptophan / Q000378:metabolism*
chemical_list: D003603:Cytotoxins; D009570:Nitriles; D014230:Triazoles; D014364:Tryptophan; C446685:systhane
keywords: enantioselective metabolism; myclobutanil; primary rat hepatocytes; tryptophan metabolism