Covalent protein binding and tissue distribution of houttuynin in rats after intravenous administration of sodium houttuyfonate
Aim: To investigate the potential of houttuynin to covalently bind to proteins in vitro and in vivo and to identify the adduct structures. Methods: Male Sprague-Dawley rats were intravenously injected with sodium houttuyfonate (10 mg/kg). The concentrations of hout- tuynin in blood, plasma and five...
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Veröffentlicht in: | Acta pharmacologica Sinica 2012-04, Vol.33 (4), p.568-576 |
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Sprache: | eng |
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Zusammenfassung: | Aim: To investigate the potential of houttuynin to covalently bind to proteins in vitro and in vivo and to identify the adduct structures. Methods: Male Sprague-Dawley rats were intravenously injected with sodium houttuyfonate (10 mg/kg). The concentrations of hout- tuynin in blood, plasma and five tissues tested were determined using an LC/MS/MS method. The covalent binding values of hout- tuynin with hemoglobin, plasma and tissue proteins were measured in rats after intravenous injection of [1-14^C]sodium houttuyfonate (10 mg/kg, 150 mCi/kg). Human serum albumin was used as model protein to identify the modification site(s) and structure(s) through enzymatic digestion and LC/MSn analysis. Results: The drug was widely distributed 10 min after intravenous injection by the heart and kidneys with significantly higher concentrations than that The lungs were the preferred site for disposition, followed n the plasma. The extent of covalent binding was correlated with the respective concentrations in the tissues, ranging from 1137 nmol/g protein in lung to 266 nmol/g protein in liver. Houttuynin reacted primarily with arginine residues in human serum albumin to form a pyrimidine adduct at 1:1 molar ratio. The same adduct was detected in rat lungs digested by pronase E. Conclusion: This study showed that the 13-keto aldehyde moiety in houttuynin is strongly electrophilic and readily confers covalent binding to tissue proteins, especially lung proteins, by a Schiff's base mechanism. The findings explain partially the idiosyncratic reactions of houttuyniae injection in clinical use. |
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ISSN: | 1671-4083 1745-7254 |
DOI: | 10.1038/aps.2011.174 |