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    • The potent inhibition of aromatase by ziram indeed caused

    2023-04-17

    The potent inhibition of aromatase by ziram indeed caused the lower estradiol production in JEG-3 cells (Fig. 4), confirming that ziram can penetrate the cell membrane to get into the cells to act. However, the treatment of ziram did not lower progesterone production in JEG-3 cells (Fig. 4), indicating that ziram does affect human HSD3B1. In JEG-3 cells, progesterone can be formed endogenously. The formation of progesterone is involved in another important P450 enzyme, cholesterol side-chain enzyme, which is located in the mitochondria and catalyzes the production of pregnenolone from the substrate cholesterol. Since the treatment of ziram did not lower progesterone level in JEG-3 cells, this indicates that ziram does not affect cholesterol side-chain enzyme activity either. In this study, we demonstrated that ziram could potently inhibit estradiol production in JEG-3 cells even at 100nM. Nevertheless, these observations are relevant to public health, because ziram occurs in the environment at comparable levels. Wang et al. reported a case–control study for Californian population to investigate the relationship between the incidence of Parkinsons’ disease and the exposures of ziram, maneb and paraquat and found that ziram could increase the incidence of Parkinson’s disease [25]. The exposure of ziram may also cause human reproduction-related diseases and more studies are required to address this issue. Serum ziram level also depends on the metabolism. Ziram was extensively metabolized in the liver. After rat exposed to ziram, body tissues contained tetramethylthiourea, the methylamine salt of dimethyldithiocarbamic acid, carbon disulfide, and methylamine, indicating that ziram is transformed in the liver into dimethyldithiocarbamic acid. Dimethyldithiocarbamic AH 7614 is subsequently coupled to give thiram or is broken down to carbon disulfide and dimethylamine [26].
    Introduction Breast cancer is one of the most common cancers found in women worldwide. Estrogens have been noted for their roles in pathogenesis and progress of the hormone-dependent (estrogen-receptor positive or ER+) breast cancer [1]. The amount of biosynthesized estrogen products involves in the final step conversion of androgens to estrogens, which is catalyzed by the key rate-limiting enzyme namely aromatase [1], [2], [3], [4], [5], [6]. Currently, there are two main types of drugs that are used for the treatment of hormone-dependent breast cancer i.e., the drugs acting on the estrogen receptor (selective estrogen receptor modulators) and the drugs that inhibit activity of the aromatase enzyme (aromatase inhibitors or AIs) [1]. The inhibition of aromatase enzyme activity is considered to be a selective strategy to decrease the amount of estrogen production without affecting the production of other steroids in the estrogen biosynthetic pathway [1]. AIs can be classified based on their mechanisms of action into two types i.e., steroidal and nonsteroidal aromatase inhibitors. The steroidal AIs are androstenedione (ASD) analogs which interact irreversibly to the active site of the aromatase either by a mechanism-based or by a competitive manner via covalent interactions, whereas the nonsteroidal AIs bind to the aromatase active site by reversible process through noncovalent interaction [3], [6]. Although the clinically available drugs for treatment of ER+ breast cancer have been proven as highly effective, their side effects and resistance in prolonged treatment persist [7], [8], [9], [10]. Thus, the improvement of the hormone-dependent breast cancer drugs still remains an energetic field of study as established in a number of recent publications [11], [12], [13], [14]. Thiourea and its derivatives have a wide range of versatile applications in many fields including medicine, agriculture and analytical chemistry. Compounds bearing thiourea scaffold hold a broad spectrum of biological activities such as anticancer [15], [16], antimalarial, antiviral and antimicrobial activities [17]. The thiourea pharmacophore possesses specific binding sites known as hydrogen binding area (NH), complementary area (S) and auxiliary binding area (1,3-substituents) [17]. Many thiourea analogs have been shown to exert potent anti-breast cancer activity [18], [19], [20], [21], [22], [23], [24], [25]. For example, 1-(chrysen-6-yl)-3-(4-nitrophenyl)thiourea (SL-1-18) 1 (Fig. 1) has been reported to inhibit proliferation of two ER+ breast cancer cell lines MCF-7 and T-47D with GI50 values of 3.72 and 2.52 µM, respectively. The growth inhibitory effect of the SL-1-18 was due to its ability to promote downregulation and degradation of the ERα as well as to block the cancer cell cycle [25]. Although an aromatase inhibitory effect of thiourea derivatives has not been reported in the literature, many compounds bearing N, O and S electron donor atoms have been reported to display aromatase inhibitory effect [1], [2]. It could be hypothesized that thiourea bearing N and S electron donors might exert aromatase inhibitory activity.