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  • The inhibition of CYP activity by NOR

    2021-03-02

    The inhibition of CYP11β activity by NOR was 11- and 2.5-fold higher than those reported for the antifungal agents ketoconazole (IC50: 4.4μM) and clotrimozole (IC50: 1.0μM) (Fernandes and Porte, 2013). Furthermore, NOR was able to inhibit P450 aromatase activity in carp ovaries, although at a rather high concentration (500μM) if compared with other synthetic chemicals, such as drugs (aminoglutethimide, IC50: 37μM), polycyclic musks (galaxolide, IC50: ∼100μM) and fungicides (clotrimazole, IC50: 7nM; ketoconazole, IC50: 1.9μM; difenoconazole, IC50: 29μM; triadimenol, IC50: 26μM; fenarimol, IC50: 18μM; prochloraz, IC50: 7.2μM) (Ankley et al., 2005, Hinfray et al., 2006, Schnell et al., 2009, Fernandes and Porte, 2013). Interestingly, a number of in vivo studies have confirmed the ability of some progestogens to disrupt steroid leukotriene in fish. Thus, a reduction in plasma concentrations of 11-KT and 17β-estradiol were observed in male and female fathead minnow, respectively, after exposure to 85ng/L of NOR (Paulos et al., 2010). Exposure of female zebrafish to 0.55pmol CPA/g of fish for 21 days decreased the whole body concentrations of testosterone and estradiol (Linderoth et al., 2006). Also, 3 months exposure to 1 and 10μg/L of CPA inhibited testicular development and gametogenesis in Japanese medaka (Kiparissis et al., 2003). Some of these effects seem to agree with the ability of NOR and CPA to act as inhibitors of the synthesis of oxy-androgens (Fig. 3). Incubation of mitochondria and microsomes isolated from mature ovaries with 17P4 lead to the formation of 17α,20α/β-DP, the formation of both α- and β-epimer increased concomitantly with the concentration of substrate with a predominance of the later in the mitochondrial fraction (Fig. 5). This contrasts with data by Kime et al. (1994) that reported 17α,20α-DP to be the major progestogen in carp ovaries. Nonetheless, the authors hypothesized that the oocytes were not sufficiently mature, and that at a slightly later stage of maturation, the steroidogenic pattern could have shift towards 17α,20β-DP. 20β-HSD activity has been reported in testes and ovaries of teleost fish, in both mitochondria and microsomes (Sakai et al., 1989, Kazeto et al., 2001). We have observed the highest 20β-HSD specific activity in the ovarian mitochondrial fraction, which agrees with data reported in ovaries of Japanese eels (Kazeto et al., 2001). Among the tested progestogens, only DRO and CPA acted as weak inhibitors of 20α/β-HSD activities. To the best of our knowledge there is no information on the effects of synthetic progestogens on fish gonadal 20α/β-HSD activities. However, Albertsson et al. (2010) showed an induction of the hepatic carbonyl reductase/20β-HSD A and B mRNA expression in rainbow trout caged downstream a STP, while intraperitoneal injection of NOR (0.25mg/kg) did not affect hepatic CR/20β-HSD mRNA expression. Significant amounts of endogenous 17α,20β-DP have been reported in plasma of carps during final oocyte maturation (Levavi-Zermonsky and Yaron, 1986). Moreover, 17α,20β-DP is known to play a major role in final gamete maturation in salmonids, in both males and females (Kime, 1993, Nagahama, 1997), and to act as the MIH in many other teleost fish (see reviews Nagahama, 1994, Nagahama and Yamashita, 2008). Furthermore, Nagahama and Yamashita (2008) postulated 17α,20β-DP as the key hormone for the induction of not only oocyte maturation (through membrane receptors), but also ovulation (through nuclear receptors). Consequently, any interference with the biosynthesis of this hormone may ultimately impair the reproductive success of fish. Hence, some studies have shown behavioural changes in fish exposed to LNG, DRO and gestodene, such as lack of interest of males for their spawning tiles, increase of mature spermatids and testes size; egg laying inhibition and induction of male secondary sexual characteristics in female fish (Zeilinger et al., 2009, Runnalls et al., 2013). However, more targeted studies are still required to unravel the mode of action of synthetic progestogens in fish.