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.

Applicability of the Rayleigh equation for enantioselective metabolism of chiral xenobiotics by microsomes, hepatocytes and in-vivo retention in rabbit tissues

“…3a in ref. 52 obtained the enantiomeric enrichment factor of −24 ± 2% (R 2 = 0.97). Two more test cases are reported by Xu et al .…”

“…In a second test case, Wang et al . 52 studied the degradation of the fungicide myclobutanil in hepatocytes from male Sprague–Dawley rats. The authors provided the individual first order rate constants as 0.065 h −1 for (+)-myclobutanil and 0.046 h −1 for (−)-myclobutanil.…”

Improved Chiral Separation of (R,S)-Goitrin by SFC: An Application in Traditional Chinese Medicine

“…Generally, HPLC is the most frequently used technique for preparative separation [12][13][14][15]. But when the established NPLC method was scaled up into a high-throughput way, things became less efficient due to long analytical time (about 30 min), large solvent consumption (especially nonenvironmentally friendly solvent such as -hexane), and heavy solvent recovery work.…”

Análise enantiosseletiva do praguicida miclobutanil após metabolismo in vitro por microssomas hepáticos de humanos

“…Os praguicidas atuam no controle de insetos (inseticidas), no controle de fungos (fungicidas), no combate as plantas invasoras (herbicidas), Os produtos agrícolas que mais empregam agroquímicos no Brasil, segundo a Associação Brasileira de Saúde Coletiva (ABRASCO, 2015), são: soja (40%); milho (15%); cana-de-açúcar e algodão (10% cada); cítricos (7%); café, trigo e arroz (3% cada); feijão (2%); batata (1%); tomate (1%); maçã (0,5%); banana (0,2%), que são também as culturas com maior área plantada no país(IBGE, 2017). indireta, causada pela ingestão de alimentos e água contaminados com resíduos destes(WANG et al, 2015). Como consequência, o número de mortes e de doenças crônicas, causadas por essa exposição do homem aos praguicidas é maior que um milhão por ano (AKTAR; SENGUPTA; CHOWDHURY, 2009).…”

“…Essas diferenças no tempo de meia-vida, também foram observadas em estudos de metabolismo empregando microssomas hepáticos de ratos(YAN et. al., 2014) e hepatócitos de ratos(WANG et. al., 2015), nos quais foi observada uma preferência maior Diversos estudos vêm sendo realizados a fim de avaliar a toxicidade do miclobutanil para organismos não-alvo.…”