Summary
A comparative study of specific estrogen-binding components in human and rat liver cytosol was performed. Similar to rat liver, human liver was found to contain high-affinity-low-capacity cytoplasmic estrogen binders. The apparent dissociation constants (KDS) of the [3H]estradiol-17β-binder complexes were calculated from Scatchard plots and found to be in the range of 0.3–4.3 × 10−9 mol/l and 1.0–3.8 × 10−9 mol/l for rat and human liver cytosol, respectively. For female rat liver cytosol, maximal estrogen-binding capacities (MBCs) of 33–54 fmol/mg protein were calculated. In contrast, cytoplasmic MBCs in human liver were found to be significantly lower (2.0–14.5 fmol/mg protein). In both species, specificity studies of the hepatic 17β-estradiol binders clearly indicated a requirement for estrogens. Similar to estrogen receptors of well-known target organs, the molecular species preferentially binding estrogens in rat and human liver cytosol was found to be a heat-labile protein. The estrogen binders of both species migrated to the anodic receptor region of agar gels. In contrast to rat liver cytosol, the anodic estrogen binding of which is exclusively specific, human liver cytosol exhibits only a small proportion of receptorlike binding drafted on a high background of nonspecific hormone cytosol interactions. In low-salt sucrose gradients, the estrophilic entities of rat and human liver sedimented at 4–5 S and 8–9 S. However, the ratio of 4–5S and 8–9S binding is reversed in the two species. Whereas in man the estrophilic macromolecules predominantly sediment at 4–5S, in the female rat 8–9S binding is favored. Sodium molybdate, an inhibitor of receptor degradation, failed to improve 8–9S estrogen binding in human liver cytosol. In mixed-cytosol experiments (human liver/calf uterus) it could be demonstrated that steroid degradation by hepatic cytosol is not responsible for the low estrogen binding capacities of human liver. It may be concluded that human liver contains estrogen binding components, which in some aspects resemble estrogen receptors. The low concentration of these binding entities does not seem to favor the hypothesis of an important direct regulatory control of estrogens on human liver by the classic receptor-mediated mechanism.
Zusammenfassung
In einer vergleichenden Studie wurde Lebercytosol von Mensch und Ratte auf die Anwesenheit spezifisch östrogenbindender Komponenten hin untersucht. Ähnlich wie in der Rattenleber konnten auch in der menschlichen Leber hochaffine sättigbare Östrogenbinder nachgewiesen werden. Die nach der Methode von Scatchard berechneten Dissoziationskonstanten (KD's der [3H]17β-Östradiol-Binder-Komplexe) lagen bei der Rattenleber im Bereich von 0,3–4,3 × 10−9 mol/l, bei der menschlichen Leber im Bereich von 1,0–3,8 × 10−9 mol/l. Die maximale Östrogenbindungskapazität (MBC) des Rattenleber-cytosols lag zwischen 33 und 54 fmol/mg Protein. Im Gegensatz dazu wurden für die menschliche Leber deutlich geringere MBC-Werte ermittelt (2,0–14,5 fmol/mg Protein). Untersuchungen der Bindungsspezifität des hepatischen 17β-Östradiolbinders zeigten in beiden Spezies eine eindeutige Präferenz für Östrogene. Ähnlich wie Östrogenrezeptoren aus bekannten Zielorganen sind die hepatischen Östrogenbinder von Ratte und Mensch thermolabile Proteine. Die Östrogenbinder beider Species lassen sich bei der Agargel-Elektrophorese in der anodischen Rezeptorregion nachweisen. Während beim Rattenlebercytosol die anodische Östrogenbindung ausschließlich spezifisch ist, findet sich beim menschlichen Lebercytosol neben spezifischer (rezeptorähnlicher) anodischer Bindung ein hoher Anteil unspezifischer Hormonbindung. Bei Saccharosedichtegradienten-Zentrifugation sedimentieren die hepatischen östrophilen Proteine beider Species im Bereich von 4–5S und 8–9S. Allerdings ist das Verhältnis von 4–5S zu 8–9S-Bindung in beiden Species unterschiedlich. Während beim Menschen die östrophilen Makromoleküle hauptsächlich mit 4–5S sedimentieren, überwiegt bei der weiblichen Ratte die 8–9S-Bindung. Durch Natriummolybdat, einem Hemmstoff der Rezeptorproteolyse, ließ sich die Konzentration der 8–9S Östrogenbinder im menschlichen Lebercytosol nicht erhöhen. In Cytosol-Mischexperimenten (menschliche Leber/Kälberuterus) konnte nachgewiesen werden, daß die niedrige Östrogenbindungskapazität des menschlichen Lebercytosols nicht auf Steroidabbau zurückzuführen ist. Die Untersuchungen legen die Schlußfolgerung nahe, daß die menschliche Leber eine östrogenbindende Komponente enthält, die in einigen Aspekten einem Östrogenrezeptor ähnelt. Die niedrige Konzentration dieser Bindungsstellen spricht gegen einen direkten regulatorischen Einfluß von Östrogenen auf die menschliche Leber über einen klassischen Rezeptormechanismus.
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Bojar, H., Schütte, J., Staib, W. et al. Does human liver contain estrogen receptors?. Klin Wochenschr 60, 417–425 (1982). https://doi.org/10.1007/BF01735934
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DOI: https://doi.org/10.1007/BF01735934