Effect of metal ions on the stable adduct formation of 16α- hydroxyestrone with a primary amine via the Heyns rearrangement

Shinichi Miyairi, Kaoru Maeda, Tomoyuki Oe, Toyoaki Kato, Akira Naganuma

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6 Citations (Scopus)


16α-Hydroxyestrone (16α-OHE1), one of the major estrogen metabolites in humans that may plays a role in cell transformation, has been found to form stable adducts with nuclear proteins. The mechanism for the formation of a stable covalent adduct of 16α- OHE1 with protein has been postulated via the Heyns rearrangement after Schiff base formation. The Heyns rearrangement on the steroidal D-ring α-hydroxyimine was investigated using 17-(2- methoxyethylimino)estra-1,3,5(10)-triene-3,16α-diol as a model intermediate. Rates of the Heyns rearrangement and hydrolysis of the steroidal α- hydroxyimine were determined by a high-performance liquid chromatography (HPLC) simultaneously. The Heyns rearrangement was demonstrated to be optimum at pH 6.2 and the reaction rate at physiological pH, 7.3-7.5, was more than 90% of that at the optimum pH. On the other hand, modulator(s) to the reactions were also examined. According to our previous finding of the proton-mediated mechanism of the Heyns rearrangement, the effects of cationic metal ions on the reactions were examined with 29 metal chlorides. Five metal ions, Pt4+, Cu2+, Ni2+, Co2+, and Mn2+, suppressed the formation of Heyns product significantly while Fe2+, Y3+, Gd3+, and Er3+ slightly increased it. The suppression rate was synergistically enhanced by the combination of Pt4+ with Co2+, Cu2+, or Ni2+. These results suggest the five metal ions, Pt4+, Cu2+, Ni2+, Co2+, and Mn2+, reduce the formation of the Heyns product in vivo and, therefore, would be useful tools to clarify the implication of the stable adduct formation of 16α-OHE1 with protein.

Original languageEnglish
Pages (from-to)252-258
Number of pages7
Issue number4
Publication statusPublished - 1999 Apr


  • 16α-Hydroxyestrone
  • Heyns rearrangement
  • Metal ion effect
  • Reduction of the adduct formation
  • Stable adduct
  • Steroidal D-ring α-hydroxyimine

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Endocrinology
  • Pharmacology
  • Clinical Biochemistry
  • Organic Chemistry


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