Finasteride synthesis After exposure to P lima expression le

After exposure to P. lima, Finasteride synthesis level of CYP3A4 and CYP2D14-like was found to be altered in gill and digestive gland, whereas OA content was found to be increased in gill and digestive gland which was in accordance with the previous report (Bauder et al., 2001; Rossignoli and Blanco, 2008; Huang et al., 2015). Similarly, Vidal et al. (2014) demonstrated a significant increment in cytochrome P450 reductase activity and OA accumulation in M. galloprovincialis exposed to the DSP toxins-producing microalgae D. acuminata and D. acuta. Huang et al. (2015) reported that CYP450 in the gills of bivalves exposed to P. lima significantly increased. These outcomes suggested that CYP450 could play a crucial role in the metabolism of DSP toxins in bivalve. However, the expression of CYP3A1 didn\'t show significant modulation in the mussels exposed to P. lima, demonstrating different regulations and responses of different types of CYP450 genes to specific chemicals. Actually, many papers have discussed these phenomena. After exposure to β-naphthoflavone (BNF) and 3,3′,4,4′,5-polychlorinated biphenyl (PCB126), CYP3-like-2 mRNA was significantly up-regulated in gill by BNF, and up-regulated in digestive gland by PCB126, whereas there was no significant change observed in the expression of CYP1-like in M. edulis (Zanette et al., 2013). CYP3A-like-1 transcript level significantly decreased after exposure to 17 beta-estradiol and tributyltin, but CYP3A-like-2 did not experience any changes in M. edulis (Cubero-Leon et al., 2012). Among the CYP450 enzymes, CYP2D has been considered a crucial protein that involves in the metabolism of xenobiotics and drugs (Zanger and Schwab, 2013). Some isoforms of the CYP2D subfamily have been well characterized, such as CYP2D6 due to its clinical importance and CYP2D14 in black cattle (Hamamoto et al., 2016; Feng and Liu, 2018). However, there are very few reports available on the characterization of CYP2D in bivalves, particularly their mechanistic role. In our study, we found that the expression of CYP2D14-like in digestive gland and gill tissue significantly altered after exposure to P. lima, suggesting that CYP2D14-like might be involved in the metabolism of OA. Besides, CYP2C8 in gill and CYP3L3 in digestive gland also exhibited altered expression, implying their potential role in DSP toxins metabolism which is in accordance with the previous report in mammals (Naraharisetti et al., 2010), and bivalves (de Boissel et al., 2017). Together, these findings uncovered the novel regulatory role of CYP450 on OA metabolism and provided the research topic for further study. CYP3A enzymes exemplify a first line of defense for mammals against the bioaccumulation of lipophilic substances by detoxifying the drugs, insecticides and carcinogens (Hegelund and Celander, 2003; James et al., 2005). Amongst, CYP3A4 is considered a potential candidate in metabolizing a variety of xenobiotics and clinical drugs (Kumagai et al., 2016). It has been reported that human CYP3A4 could efficiently hydrolyze OA into four metabolites in an in vitro experiment (Guo et al., 2010). CYP3A4 and CYP3A5 have been shown to mainly catalyze the metabolism of OA into oxygenated metabolites (Kittler et al., 2014; Kolrep et al., 2016). Interestingly, previous study showed that inhibition of CYP3A4 activity by ketoconazole could enhance the toxic effects of these toxins despite OA, DTX-1 and DTX-2 did not increase CYP450 (1A2, 3A4, 2C9, 2C19) activities in HepaRG cells (Ferron et al., 2016). Collectively, our findings demonstrated that the expression of CYP3A4 was significantly up-regulated after exposure to P. lima, thereby suggesting the crucial role of CYP3A4 in the metabolism of OA which is in line with the aforementioned reports.