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  • Xenobiotic metabolism primarily occurs in liver


    Xenobiotic metabolism primarily occurs in liver, which contains many enzymes to catalyze the transformation of xenobiotic. Usually, cytochrome P-450s (CYP450s) act as the first response for biotransformation of xenobiotic in organisms. CYP450s generally consist of various subfamily enzymes which can catalyze different reactions of xenobiotic (Tang et al., 2006). Previous studies have revealed that the effects of a Diperodon HCl varied among CYP450 enzymes, indicating that the effects of a compound on CYP450s were enzyme-specific. CYP450 enzyme-specific metabolism has been reported for some pollutants such as PCB, dioxins and other xenobiotics (Guengerich, 2001, Lu et al., 2013, Vijaya Padma et al., 2014). The findings suggest that a compound could be catalyzed by one or several specific CYP450 enzymes during its metabolism by CYP450s (Guengerich, 2008). Therefore, CYP450 enzyme-specific interaction with pollutants provides us to better understand the pathway of metabolism of pollutants. Metalaxyl is a chiral pesticide with a stereogenic center in the carboxy alkyl moiety, and thus consists of a pair of enantiomers (Fig. S1, Supporting Material). Since first introduced in 1977, metalaxyl has been widely used as a fungicide to control diseases caused by Oomycetes on a wide range of plants including crops for more than thirty years (Li et al., 2013, Monkiedje et al., 2003). With the wide application, metalaxyl has been detected in many environmental matrixes, including water, soil, and sediment as well as organisms (Martin et al., 2012, Monkiedje et al., 2003, Sanchez-Gonzalez et al., 2013, Wani et al., 2012, Wightwick et al., 2012). Although metalaxyl was used as a racemic mixture (ER=1), the enantioselective accumulation of metalaxyl has been reported in organisms and found to vary among the organisms (Wang et al., 2014, Xu et al., 2011, Zhang et al., 2012). However, the mechanisms for species-specific enantioselective biotransformation of metalaxyl have never been investigated. Although CYP450s consist of various subfamily enzymes, only some of them have been well studies relating to metabolism of xenobiotics such as CYP1A1, CYP1A2, CYP2B1, CYP2B2, CYP2E1, and CYP3A (Guengerich, 2001, Lu et al., 2013, Oropeza-Hernández et al., 2003; Vijaya Padma et al., 2014). In this study, therefore, the effects of metalaxyl on the six CYP450 enzymes were investigated in four vertebrate hepatic cell lines, including human hepatic HepG 2 cells, rat hepatic H4IIE cells, chicken hepatic LMH cells and grass carp hepatic L8824 cells. The residual concentrations and ER of metalaxyl were also determined in the medium of the four cells to reveal the enantioselective species-specific responses of CYP450s for metalaxyl.
    Materials and methods
    Discussion In addition, the responses of CYP450s induced by metalaxyl are species-specific in the four cells. For example, metalaxyl lead to induction of CYP1A1, CYP1A2, and CYP2B1 in HepG2 cells, CYP1A2 and CYP2B1 in H4IIE cells, CYP1A1 and CYP2B1 in LMH cells, and CYP2B1 in L8824 cells. Generally, increased CYP450 enzymes induced by a xenobiotic should promote the catalysis of the xenobiotic to intermediates (Nebert et al., 1990). Furthermore, CYP450 enzyme-specific catalysis of xenobiotic indicates different metabolic pathways due to the variation of CYP450 enzymes in sort and structure (Guengerich, 2008). Therefore, the observation in the present study may suggest that metalaxyl is metabolized by different CYP450 enzymes in the four cells through various catalytical pathways. The suggestions were, at least in part, confirmed by the hindrance of attenuation of metalaxyl in the medium when the specific inhibitors were added. The biotransformation of metalaxyl has been reported in several species of organisms and the metabolites were identified in these studies (Abass et al., 2007, Li et al., 2013, WHO, 2002). Arguably, the metabolites of metalaxyl varied among the species. Li et al. (2013) reported that the major metabolite of metalaxyl was metalaxyl acid in tomato and cucumber. In rat in vivo, the predominant metabolite was didemethylmetalaxyl (WHO, 2002). Two hydroxymetalaxyl derivatives were identified as the major metabolites in human liver microsomes (WHO, 2002). Although the metabolites were not detected in the present study due to the application of cell models instead of Whole organisms and the complexity of metabolites of metalaxyl in different species, it is speculated that there were various intermediates of metalaxyl existing in the medium of the four cells. Therefore, CYP450 enzyme-specific catalysis is believed to be one of the important contributors to the diversity of metabolites of metalaxyl. In addition, there were only six CYP450 enzymes were investigated in our study, although CYP450s consists of a large of subfamily enzymes. It is hardly to exclude other CYP450 enzymes involved in the metabolism of metalaxyl in these cells.