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  • Testosterone is inactivated through hydroxylation and conjug

    2019-09-23

    Testosterone is inactivated through hydroxylation and conjugation pathways [3], [4]. 6β-Hydroxylation is the main pathway among testosterone hydroxylation processes in the liver microsome. Testosterone 6β-hydroxylation is mainly catalyzed by cytochrome P450 3A (CYP3A) [5], [6], which is expressed in the liver predominantly and is also expressed in other organs including the prostate [7], [8], [9], [10]. Recently, Zhang et al. reported that treatment with pregnenolone 16α-carbonitrile, an inducer of CYP3A, reduces either the plasma testosterone levels or prostate weights in castrated mice [11]. This finding suggests that CYP3A is one of the regulators for circulating testosterone and its effects on the prostate [11]. However, it remains unclear whether a decreased state of CYP3A activity affects the systemic level of testosterone and its effects on the prostate. Androgens enhance cholesterol synthesis in the LNCaP line of cells, an androgen-dependent prostate cancer cell line, by the following mechanism: androgens stimulate the processing of sterol regulatory element-binding protein2 (SREBP2) through AR-mediated activation of SREBP cleavage-activating protein (SCAP) gene transcription [12], [13], and activated SREBP2 increases Dioscin mass levels of genes involved in the synthesis and transport of cholesterol such as HMG-CoA synthase 1 (Hmgcs1), HMG-CoA reductase (Hmgcr), and low density lipoprotein receptor (Ldlr) [14]. However, whether androgens stimulate these processes in the in vivo prostate remains unclear. The purpose of the present study was to clarify whether a reduced state of CYP3A activity affects the systemic levels of testosterone and its effect on the prostate. To accomplish this purpose, we studied the effects of Cyp3a deficiency on circulating testosterone levels and prostatic expression levels of genes regulated by the AR using Cyp3a-knockout (Cyp3a−/−) mice. We also studied the expression levels of genes involved in cholesterol synthesis and total cholesterol content in the prostate of Cyp3a−/− mice in order to explore the possibility that activation of the AR affects cholesterol synthesis via the SCAP-SREBP2 pathway in the prostate.
    Materials and methods
    Results
    Discussion A previous report using Cyp3a−/− mice has shown that Cyp3a deficiency impaired drug metabolism dramatically [22]. We recently showed that hepatic cholesterol and bile acid synthesis were enhanced in the liver of Cyp3a−/− mice [16]. Thus, Cyp3a−/− mice are useful tools to clarify pharmacological and physiological role of CYP3A in vivo. The results of the present study showed that 6β-hydroxylation activities of testosterone were remarkably decreased in the liver microsomes of Cyp3a−/− mice, being consistent with the results of previous studies showing that inactivation of Dioscin mass testosterone into 6β-hydroxytestosterone in the liver is mainly catalyzed by CYP3A [4], [6]. Since the liver is considered to be the most important organ responsible for the catabolism of steroid hormones [23], the in vitro findings are consistent with the present in vivo results showing that total testosterone levels in the plasma and liver and free testosterone levels in plasma were significantly increased in Cyp3a−/− mice (Fig. 2A and B). These findings suggest that CYP3A, perhaps hepatic CYP3A, is one of the important determinants that regulate systemic testosterone levels in mice. In this connection, we showed that total testosterone levels were increased by 1.8 fold and that free levels were increased by 9.0 fold in the plasma of Cyp3a−/− mice. This difference appears to come from the different free fractions of testosterone in plasma, which were calculated to be 37% and 7.2% in the plasma of Cyp3a−/− and WT mice, respectively. It seemed that binding of testosterone to serum proteins, such as SHBG, is saturated because of the increased levels of testosterone in plasma of Cyp3a−/− mice. In any case, the 9.0-fold increase in levels of free testosterone indicates that total clearance of free testosterone was decreased dramatically in Cyp3a−/− mice (11% of that in WT mice), suggesting that CYP3A is a major determinant regulating systemic levels of testosterone at least in mice.