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  • The role of ARA cyp metabolites in the


    The role of ARA-cyp450 metabolites in the liver is still unclear [44]. However, ARA-cyp450 genes metabolize other fatty acids such lauric and palmitic 51 8 [45]. It was found that decreased cyp4a expression caused fatty livers through reduction of fatty acid metabolism [46]. In this study, we found that NSAIDs, but not diclofenac, downregulated expression of all cyp450 genes tested in the hepatic tissues. This finding is in parallel with the accumulation of fat in the liver and with the fatty change seen by the microscopic examination. These results may indicate that downregulation of hepatic ARA-cyp450 genes is involved in the hepato-toxicity induced by NSAIDs.
    Author contribution
    Acknowledgments This work was supported by King Abdullah II Fund for Development (Amman, Jordan) with a grant fund number of 6-2018.
    Introduction Myclobutanil (MCL), (RS)-2-(4-chlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)hexanenitrile (Fig. 1), is a broad-spectrum systemic triazole fungicide with protective, eradicative, and curative action (University of Hertfordshire, 2018). It is employed to control pests such as powdery mildew, dollar spot, summer patch, rusts, and scab in perennial and annual crops, turf, landscape ornamentals, fruit trees, and vines worldwide (University of Hertfordshire, 2018). Its antifungal activity is related to disrupted fungal membrane function resulting from inhibited sterol biosynthesis (University of Hertfordshire, 2018). MCL bears an asymmetric carbon, so it is a chiral molecule (Fig. 1). Therefore, there may be significant enantioselective differences in the activities of the MCL racemic mixture and of the isolated MCL enantiomers toward target organisms. The MCL enantiomers have already had their enantioselective antifungal actions evaluated against Physalospora piricola (Deng and Hu, 2011), Gibberella zeae (Deng and Hu, 2011), Alternaria kukuchiana (Deng and Hu, 2011), Alternaria solani (Deng and Hu, 2011), Cercospora arachidicola, Fulvia fulva (Sun et al., 2014), and Phytophthora infestans (Sun et al., 2014). For all the evaluated species, (+)-MCL presented higher antifungal activity than (−)-MCL or the racemic mixture (Deng and Hu, 2011; Sun et al., 2014). Notwithstanding the proven differences between the activities of MCL enantiomers, this fungicide is still sold as a racemic mixture. Significant potential differences among pesticide enantiomers may warrant registration of a single enantiomer product or an enriched mixture of the active enantiomer instead of the racemic mixture (Liu and Tang, 2011). In Switzerland and the Netherlands, pesticides like mecoprop and dichlorprop have been registered as single enantiomer products because the R-enantiomers have greater herbicidal activity than the S-enantiomers (Liu and Tang, 2011). Replacement of a racemic mixture with a single enantiomer product or an enriched mixture of the active enantiomer is intended to reduce the amount of pesticide use in the field, consequently lowering the risk of contamination and toxic effects on non-target species, mainly humans (Liu and Tang, 2011). MCL is moderately toxic to humans (class II) (Sun et al., 2014). It can cause hepatic toxicity, disrupt steroid homeostasis, and affect the reproductive system in animals (Sun et al., 2014). Because MCL persists in the environment, it can accumulate in the food chain, thereby representing a great risk to the human health (Sun et al., 2014). Several papers have reported that MCL residue is present in food (Freeman et al., 2016), water (Zhao et al., 2018), and air (Di Filippo et al., 2018), and MCL has been detected in a controlled baby food simulation study (Kovacova et al., 2014). Therefore, assessing MCL risks in humans is extremely important to provide reliable scientific information regarding the human health (Abass, 2013). Chiral pesticides may behave with significant enantioselectivity toward non-target organisms, including humans (Drăghici et al., 2013). Therefore, evaluating how MCL interacts with non-target organisms from an enantioselective standpoint is essential to assess its risks (Drăghici et al., 2013). In this sense, MCL toxicity, absorption, distribution, biodegradation, bioaccumulation, and metabolism must be investigated (Drăghici et al., 2013). The toxicity of MCL enantiomers to aquatic algae (Scenedesmus obliquus) (Cheng et al., 2013; Li et al., 2015), crustaceans (Daphnia magna) (Li et al., 2015), lizards (Eremias argus) (Cheng et al., 2017), and zebrafish (Danio rerio) (Li et al., 2015) has already been evaluated. These studies demonstrated significant enantioselective differences in MCL toxicity, which varied depending on the evaluated species (Cheng et al., 2017, 2013; Li et al., 2015). MCL biodegradation in strawberry (Zhang et al., 2011), grape (Lin et al., 2018), cucumber (Dong et al., 2012), and soil (Dong et al., 2012) presented significant enantioselective differences, which highlighted risks of contamination and reinforced the importance of conducting enantioselective studies to assess MCL risks.