TY - JOUR
T1 - Effect of metal ions on the stable adduct formation of 16α- hydroxyestrone with a primary amine via the Heyns rearrangement
AU - Miyairi, Shinichi
AU - Maeda, Kaoru
AU - Oe, Tomoyuki
AU - Kato, Toyoaki
AU - Naganuma, Akira
N1 - Funding Information:
This work was supported in part by a grant-in-aid for Scientific Research from The Ministry of Education, Science, Sports and Culture of Japan and by a grant from Kowa Life Science Foundation.
PY - 1999/4
Y1 - 1999/4
N2 - 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.
AB - 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.
KW - 16α-Hydroxyestrone
KW - Heyns rearrangement
KW - Metal ion effect
KW - Reduction of the adduct formation
KW - Stable adduct
KW - Steroidal D-ring α-hydroxyimine
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U2 - 10.1016/S0039-128X(98)00118-4
DO - 10.1016/S0039-128X(98)00118-4
M3 - Article
C2 - 10399881
AN - SCOPUS:0032995522
VL - 64
SP - 252
EP - 258
JO - Steroids
JF - Steroids
SN - 0039-128X
IS - 4
ER -