In the present study it
In the present study, it was found that HepG2, H4IIE and LMH cells were inclined to remove S-metalaxyl and lead to decrease of ERs of metalaxyl, while L8824 cells were inclined to attenuate R-metalaxyl and resulted in an inverse shift of ER. These findings indicate the enantioselective accumulation of metalaxyl is species-specific. Enantioselective accumulation of metalaxyl has also been reported in plants and varied among species (Li et al., 2013, Wang et al., 2014). However, the enantioselective species-specific accumulation of metalaxyl was seldom compared in animals in previous studies. It was reported that the metabolism of S-metalaxyl was faster than that of R-metalaxyl in rat and rabbit hepatic microsomes (Zhang et al., 2012). On the contrary, Xu et al. (2011) found that invertebrate earthworm was inclined to accumulate S-metalaxyl. Comprehensively considering together, it is speculated that the metabolism of S-metalaxyl may be faster than R-metalaxyl in higher animals such as mammals and birds, and slower than R-metalaxyl in lower animals such as invertebrates and fish.
The enantioselective species-specific accumulation of metalaxyl is believed to lead to the difference in toxicity outcomes among organisms due to the different toxicities of the enantiomers. In most of previous studies, the toxicity of R- metalaxyl was found to be greater than S- metalaxyl either in targeted and non-targeted organisms (Chen and Liu, 2008, Yao et al., 2009, Zadra et al., 2002) Therefore, the accumulation of metalaxyl might show more potential of toxicity in mammals and ic propranolol than in fish since mammals and birds are inclined to metabolize S-metalaxyl. But a reverse toxicity for the enantiomers of metalaxyl was also reported in earthworm in which R-metalaxyl possess less toxicity than S-metalaxyl (Xu et al., 2011), indicating that enantioselective toxicity of metalaxyl might also be species-specific. Therefore, it is suggested that enantioselective species-specific accumulation and enantioselective species-specific toxicity should be both considered when assessing the risk of residue of metalaxyl in organisms.
Although enantioselective accumulation of metalaxyl in organisms is an integrated outcome of bio-process including absorption, transportation, and transformation, it is observed in our study that catalysis of CYP450 may lead to the enantioselective accumulation of metalaxyl. However, the mechanisms on enantioselective accumulation of metalaxyl involving CYP450 are still far away from full disclosure. Enantioselective interaction with CYP450 has been reported for some pollutants in organisms (Kania-Korwel et al., 2008, Lu et al., 2011). Kania-Korwel et al. (2008) revealed that (+)-PCB 136 had stronger ability to bind to CYP450 enzymes such as CYP2B and CYP3A compared to (-)-PCB 136. (S)-naringenin was 2-fold more potent to inhibit CYP19 and CYP2C19 than (R)-naringenin, while (R)-naringenin was 2-fold more inhibitory potent for CYP2C9 and CYP3A (Lu et al., 2011). Accordingly, the enantioselective attenuation of metalaxyl observed in the present study is probably related to the enantioselective interaction of metalaxyl with CYP450. But the hypothesis has to be proven by further study.
Acknowledgements The work was financially supported by the National Nature Science Foundation of China (21677126, 21320102007) and Research Center for Air Pollution and Health, Zhejiang University.
Introduction Cytochrome P450 monooxygenases (CYPs) are an important biochemical system involved in the metabolism of xenobiotic and endogenous compounds , , . Among the various phase I and phase II drug-metabolizing enzymes, the cytochrome P450 enzymes play a key role in xenobiotic and endobiotic metabolic processing. It has been estimated that about two thirds of marketed drugs are metabolized by this enzyme system. Recombinant cytochrome P450 enzymes offer an alternative in vitro system for human metabolic clearance predictions; potential advantages include the incorporation of interindividual variation in P450 expression and added value in terms of an early understanding of drug metabolism enzymology , .