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  • In humans CYP A major isoforms of CYP As in

    2020-05-21

    In humans, CYP3A4/5, major isoforms of CYP3As in the liver, have variants that reduce the enzyme activities [33], [34]. In addition, Werk et al. recently reported the first case of a complete failure of CYP3A enzyme activity due to homozygous loss-of-function mutation of CYP3A4 combined with nonfunctional CYP3A5 [35]. Furthermore, a number of drugs used in clinical settings inhibit CYP3A activity [36]. In particular, drugs including antibacterials, anticancer agents, anti-HIV agents, antihypertensives, sex steroids and their receptor modulators, and several herbal constituents cause potent and sustained inhibition of CYP3A [37], since they make CYP3A completely nonfunctional until it is replaced with newly synthesized one. Therefore, further studies are needed to clarify the effects of genetic mutations of CYP3A genes and treatments with these CYP3A-inhibiting drugs on systemic levels of free testosterone and their potential associations with prostate cancer and benign prostate hypertrophy in humans, as well as in disease model mice such as the transgenic adenocarcinoma of mouse prostate model.
    Conclusion We studied the effects of Cyp3a deficiency on circulating testosterone levels and their effects on the prostate using Cyp3a−/− mice. Cyp3a deficiency dramatically increased plasma testosterone levels, suggesting that CYP3A is a major determinant regulating systemic levels of testosterone at least in mice. The results also indicated that Cyp3a deficiency stimulated androgen response via AR activation in the prostate. Finally, Cyp3a deficiency increased cholesterogenic gene expression levels and total cholesterol contents in the prostate, which may be caused by activation of the SCAP-SREBP2 pathway.
    Conflict of interest
    Funding This work was supported in part by JSPS KAKENHI Grant Number 15K08067 (K.K.).
    Introduction The activities of drug-metabolizing Flavopiridol hydrochloride receptor undergo marked changes during pregnancy, which alters the pharmacokinetics of drugs. Physiological changes during pregnancy can also influence drug absorption, distribution, metabolism, and excretion [1]. A previous study reported that about 90% of pregnant women in the United States took one or more medications during pregnancy, and 70% took medications during the first trimester [2]. The dosage of these drugs during pregnancy must be carefully adjusted based on changes in pharmacokinetics for therapeutic efficacy as well as for maternal, fetal, and neonatal safety. However, information regarding the pharmacokinetics and pharmacodynamics of drugs in pregnant women is lacking because of various safety issues. The phase I drug-metabolizing enzyme cytochrome P450 (CYP) is essential for metabolizing drugs and endogenous substrates [3]. Among the CYPs, CYP3A is the most abundant in human liver and accounts for the metabolism of more than 50% of currently prescribed drugs [4]. Previous studies involving several CYP3A substrates such as midazolam, dextromethorphan, clorazepate, and protease inhibitors have suggested that CYP3A activity is increased during pregnancy [5], [6], [7], [8], [9]. CYP3A activity has also been reported to be significantly induced by approximately twofold during the third trimester, as determined based on orally administered midazolam clearance in the third trimester compared with that in postpartum [9]. In all three trimesters, an apparent increase in CYP3A activity of about 1.3-fold has also been observed using the urinary dextromethorphan/3-hydroxymorphinan metabolic ratio; however, the influence of the predominant metabolizer of dextromethorphan, CYP2D6, on metabolizing dextromethorphan should not be ignored in this case [7]. CYP3A activity shows large inter-individual variations, which can lead to high variability in the therapeutic efficacy of various drugs between patients with the same prescription [3]. One of the most important subpopulations of pregnant women that requires CYP3A substrate drugs is pregnant women infected with human immunodeficiency virus (HIV). To prevent the transmission of HIV to the unborn child and to safeguard the health of the mother, antiretroviral therapy during pregnancy is essential, and most antiretroviral drugs are metabolized by CYP3A [10]. In addition, 17-alpha hydroxyprogesterone caproate is used in pregnant women to reduce preterm birth rates, and its plasma concentration is highly dependent on CYP3A activity [11]. Therefore, the assessment of CYP3A activity is essential for developing individualized therapies in such populations of pregnant women [12].