Oestrogen-receptors (ER) are likely to be promiscuous: wider role for oestrogens and mimics.
The anti-breast cancer drug tamoxifen that binds to ER is metabolised in human liver by CYP2D6 isoenzyme, whilst the metabolism of 17beta-oestradiol (by hydroxylation) is by phase I biotransformation in the liver to 2-hydroxyoestradiol and to 4-hydroxyoestradiol respectively by two isoenzymes of this mixed function oxidase CYP cytochromes P450 (EC 1.14.14.1); CYP1A2 and by CYP1B1. Nevertheless, it appears that the receptor (AhR) itself causes the expression of oestrogen-regulated target genes (studied by binding of dioxin). This is the result of an unknown signalling mechanism at the genome that is triggered directly by this receptor by binding promiscuously to ER (alpha or beta) sites. This has been observed even in the absence of oestrogens or mimics therefore in genome-binding investigations of target tissues such as uterus: oestrogen-receptor (ER) is likely to be promiscuous therefore. Furthermore, AhR (polycyclic aromatic hydrocarbon receptor), when activated by the binding of aromatic hydrocarbons (Ah) forms a complex with the aryl hydrocarbon nuclear-translocator chaperone protein (Arnt). It is this binding to xenobiotic response elements in DNA that initiates expression of the appropriate oestrogen-regulated target-genes in the uterus and other target tissues (including mammary, ovaries, and brain). The likely promiscuity of oestrogen receptors is proposed to be the cause of numerous side effects when oestrogen is involved in therapy, these can be manifest in hormone replacement therapy (HRT) and in the incorporation of synthetic oestrogens in the wide varieties of oral contraceptives now available.
Wiseman
Alan
A
School of Biomedical and Molecular Sciences, University of Surrey, Guildford GU2 7XH, UK. alan@tridgway.wanadoo.co.uk
D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D006841:Hydrocarbons, Aromatic / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D011485:Protein Binding; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D014599:Uterus / Q000378:metabolism
D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D051792:Basic Helix-Loop-Helix Proteins; D003577:Cytochrome P-450 Enzyme System; D004967:Estrogens; D006841:Hydrocarbons, Aromatic; D018336:Receptors, Aryl Hydrocarbon; D011960:Receptors, Estrogen; C111235:AHR protein, human; C497396:ARNT protein, human