title: Luteolin is a rare substrate of human catechol-O-methyltransferase favoring a para-methylation.
abstract: METHODS
  The study aimed to investigate the regioselectivity of methylation of luteolin (3',4',5,7-tetrahydroxyflavone) in human in vitro and in vivo.
  
  
  RESULTS
  Recombinant human catechol-O-methyltransferase (COMT) and human liver S9 were utilized to study the kinetics of meta (3')- and para (4')- methylation of luteolin, and urine samples from volunteers after giving a luteolin-containing formulation were collected to determine the ratio of para-/meta-production. The results showed luteolin favored a para-methylation, with a ratio of of para-/meta-production in CLint (1.43 in recombinant human COMT and 1.47 in human liver S9), which was contrary to the known substrates of COMT. However, the result of urine sample assay showed a preference of meta-methylation with a ratio of of para-/meta-production (0.460 ± 0.126). To elucidate the mechanism for different preference of methylation of luteolin in vitro and in vivo, metabolism stability of the meta- and para-methylated luteolin was evaluated in human liver microsomes and recombinant human CYP450s, which revealed that para-methylated luteolin was more easily demethylated by human CYP1A2 and CYP3A4/5 than meta-methylated luteolin.
  
  
  CONCLUSIONS
  Luteolin was a rare substrate of human COMT favoring a para-methylation, but further demethylation by human CYP1A2 and CYP3A4/5 caused a preference of accumulation in meta-methylated luteolin in vivo.
authors: Department of Pharmaceutical Analysis and Drug Metabolism, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, PR China.
authors: Zhong-Jian
authors: ZJ
authors: Chen
authors: Yan-Qing
authors: YQ
authors: Dai
authors: Si-Si
authors: SS
authors: Kong
authors: Fei-Feng
authors: FF
authors: Song
authors: Li-Ping
authors: LP
authors: Li
authors: Jian-Feng
authors: JF
authors: Ye
authors: Ru-Wei
authors: RW
authors: Wang
authors: Su
authors: S
authors: Zeng
authors: Hui
authors: H
authors: Zhou
authors: Hui-Di
authors: HD
authors: Jiang
mesh_terms: D000284:Administration, Oral; D000328:Adult; D002394:Catechol O-Methyltransferase / Q000378:metabolism*; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D005260:Female; D006801:Humans; D008099:Liver / Q000378:metabolism; D047311:Luteolin / Q000494:pharmacology* / Q000652:urine; D008297:Male; D008745:Methylation; D008862:Microsomes, Liver / Q000378:metabolism; D011994:Recombinant Proteins
chemical_list: D011994:Recombinant Proteins; C504573:CYP1A2 protein, human; C510164:CYP3A5 protein, human; D019388:Cytochrome P-450 CYP1A2; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D002394:Catechol O-Methyltransferase; D047311:Luteolin