Cytochrome P450 enzymes that metabolize estrogens are expressed in the mammary gland, uterus, brain and other target tissues for estrogen action, and this results in the formation of hydroxylated estrogens in these tissues. Estradiol metabolites formed in target tissues at or near estrogen receptors may either be inactive or have important biological effects, and changes in the activities of estrogen-metabolizing enzymes in target tissues may profoundly influence estrogen action. Although some active estrogen metabolites exert hormonal effects in target tissues by interaction with the classical estrogen receptor, other metabolites appear to elicit unique biological responses that are not associated with activation of this receptor. Therefore, some of the many actions of estradiol may not be caused by estradiol per se, but may result from the formation of active estrogen metabolite(s) which function as local mediators or may activate their own unique receptors or effectors. This is an important area in need of more research. The present paper represents a review of the literature and perspectives by the authors on the functional role of estrogen metabolism in target tissues.

https://www.hormonebalance.org/images/documents/Zhu%2098estrogen%20metabolism%20in%20target%20cells%20Carc.pdf

Functional role of estrogen metabolism in target cells: review and perspectives.

This chapter is an update of the data on substrates, reactions, inducers, and inhibitors of human CYP enzymes published previously by Rendic and DiCarlo (1), now covering selection of the literature through 2001 in the reference section. The data are presented in a tabular form (Table 1) to provide a framework for predicting and interpreting the new P450 metabolic data. The data are formatted in an Excel format as most suitable for off-line searching and management of the Web-database. The data are presented as stated by the author(s) and in the case when several references are cited the data are presented according to the latest published information. The searchable database is available either as an Excel file (for information contact the author), or as a Web-searchable database (Human P450 Metabolism Database, www.gentest.com) enabling the readers easy and quick approach to the latest updates on human CYP metabolic reactions.

Summary of information on human cyp enzymes: human p450 metabolism data

The major function of the placenta is to transfer nutrients and oxygen from the mother to the foetus and to assist in the removal of waste products from the foetus to the mother. In addition, it plays an important role in the synthesis of hormones, peptides and steroids that are vital for a successful pregnancy. The placenta provides a link between the circulations of two distinct individuals but also acts as a barrier to protect the foetus from xenobiotics in the maternal blood. However, the impression that the placenta forms an impenetrable obstacle against most drugs is now widely regarded as false. It has been shown that that nearly all drugs that are administered during pregnancy will enter, to some degree, the circulation of the foetus via passive diffusion. In addition, some drugs are pumped across the placenta by various active transporters located on both the fetal and maternal side of the trophoblast layer. It is only in recent years that the impact of active transporters such as P-glycoprotein on the disposition of drugs has been demonstrated. Facilitated diffusion appears to be a minor transfer mechanism for some drugs, and pinocytosis and phagocytosis are considered too slow to have any significant effect on fetal drug concentrations. The extent to which drugs cross the placenta is also modulated by the actions of placental phase I and II drug-metabolising enzymes, which are present at levels that fluctuate throughout gestation. Cytochrome P450 (CYP) enzymes in particular have been well characterised in the placenta at the level of mRNA, protein, and enzyme activity. CYP1A1, 2E1, 3A4, 3A5, 3A7 and 4B1 have been detected in the term placenta. While much less is known about phase II enzymes in the placenta, some enzymes, in particular uridine diphosphate glucuronosyltransferases, have been detected and shown to have specific activity towards marker substrates, suggesting a significant role of this enzyme in placental drug detoxification. The increasing experimental data on placental drug transfer has enabled clinicians to make better informed decisions about which drugs significantly cross the placenta and develop dosage regimens that minimise fetal exposure to potentially toxic concentrations. Indeed, the foetus has now become the object of intended drug treatment. Extensive research on the placental transfer of drugs such as digoxin and zidovudine has assisted with the safe treatment of the foetus with these drugs in utero. Improved knowledge regarding transplacental drug transfer and metabolism will result in further expansion of pharmacological treatment of fetal conditions.

Drug transfer and metabolism by the human placenta

Cytochrome P450-mediated metabolism of estrogens and its regulation in human

The ontogeny of drug metabolism enzymes and implications for adverse drug events

Expression of the Ah receptor-regulated cytochrome P4501B1 (CYP1B1) gene was studied in human adult and fetal tissues and cells in culture by reverse transcriptase-coupled polymerase chain reaction (RT-PCR). In adults, CYP1B1 mRNA was detected in liver, lymphocytes, cells of bronchoalveolar lavage samples and uterine endometrium, but not in lung. The level of expression was very low in adult liver and only three out of six fetal livers expressed CYP1B1. Extrahepatic fetal tissues, especially brains and kidneys, expressed high levels of CYP1B1. CYP1B1 mRNA was constitutively detected at a low level in first trimester and full-term placental samples. A competitive RT-PCR assay was developed to assess the regulation of CYP1B1. CYP1B1 mRNA was not induced in placenta by maternal cigarette smoking. Inducibility of CYP1B1 in cells in culture by the Ah receptor ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin was studied in primary fibroblasts and chorion carcinoma cell line JEG-3 having different CYP1A1 induction properties. Inducibility of CYP1B1 was found to be regulated independently from CYP1A1. In JEG-3 cells CYP1A1 mRNA was induced up to 9000-fold, while the expression of CYP1B1 was not affected. Expression of Ah receptor and Ah receptor nuclear translocator (regulators of the CYP1 family) was determined in human placenta and in the JEG-3 cell line. Expression of these transcription factors was found neither to be co-regulated nor affected by Ah receptor ligands. This study provides evidence that in addition to the Ah receptor complex, other cell-specific factors modulate the response of CYP1B1 and CYP1A1 to Ah receptor ligands.

Expression of CYP1B1 in human adult and fetal tissues and differential inducibility of CYP1B1 and CYP1A1 by Ah receptor ligands in human placenta and cultured cells.

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Expression of CYP1B1 in human adult and fetal tissues and differential inducibility of CYP1B1 and CYP1A1 by Ah receptor ligands in human placenta and cultured cells.