title: Covalent protein binding and tissue distribution of houttuynin in rats after intravenous administration of sodium houttuyfonate.
abstract: OBJECTIVE
  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 houttuynin in blood, plasma and five tissues tested were determined using an LC/MS/MS method. The covalent binding values of houttuynin 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/MS(n) analysis.
  
  
  RESULTS
  The drug was widely distributed 10 min after intravenous injection. The lungs were the preferred site for disposition, followed by the heart and kidneys with significantly higher concentrations than that in 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.
  
  
  CONCLUSIONS
  This study showed that the β-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.
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, China.
authors.forename: Zhi-peng
authors.initials: ZP
authors.lastname: Deng
authors.forename: Da-fang
authors.initials: DF
authors.lastname: Zhong
authors.forename: Jian
authors.initials: J
authors.lastname: Meng
authors.forename: Xiao-yan
authors.initials: XY
authors.lastname: Chen
mesh_terms: D000473:Alkanes / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics*; D000818:Animals; D007275:Injections, Intravenous; D008297:Male; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013447:Sulfites / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics*; D014018:Tissue Distribution
chemical_list: D000473:Alkanes; D011506:Proteins; D013447:Sulfites; C473296:sodium houttuyfonate