Effect of metal ions on the stable adduct formation of 16alpha-hydroxyestrone with a primary amine via the Heyns rearrangement.
16alpha-Hydroxyestrone (16alpha-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 16alpha-OHE1 with protein has been postulated via the Heyns rearrangement after Schiff base formation. The Heyns rearrangement on the steroidal D-ring alpha-hydroxyimine was investigated using 17-(2-methoxyethylimino)estra-1,3,5(10)-triene-3,16alpha-dio l as a model intermediate. Rates of the Heyns rearrangement and hydrolysis of the steroidal a-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 16alpha-OHE1 with protein.
Department of Molecular and Biochemical Toxicology, Faculty of Pharmaceutical Sciences, Tohoku University, Sendai, Japan. miyairi@mail.pharm.tohoku.ac.jp
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Miyairi
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Maeda
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Oe
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Kato
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Naganuma
D002412:Cations; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002851:Chromatography, High Pressure Liquid; D003035:Cobalt / Q000494:pharmacology; D003300:Copper / Q000494:pharmacology; D004355:Drug Stability; D004910:Erythrocyte Membrane / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D006894:Hydroxyestrones / Q000737:chemistry* / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D008670:Metals / Q000494:pharmacology*; D015394:Molecular Structure; D009532:Nickel / Q000494:pharmacology; D010984:Platinum / Q000494:pharmacology; D012709:Serum Albumin / Q000378:metabolism; D013329:Structure-Activity Relationship
D002412:Cations; D006894:Hydroxyestrones; D008565:Membrane Proteins; D008670:Metals; D012709:Serum Albumin; C026702:16-hydroxyestrone; D003035:Cobalt; D010984:Platinum; D003300:Copper; D009532:Nickel