Effect of genetic polymorphism on the metabolism of endogenous neuroactive substances, progesterone and p-tyramine, catalyzed by CYP2D6

Toshiro Niwa, Toyoko Hiroi, Daisuke Tsuzuki, Shigeo Yamamoto, Shizuo Narimatsu, Tsuyoshi Fukuda, Junichi Azuma, Yoshihiko Funae

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

Metabolic activities toward endogenous substrates in the brain, progesterone and p-tyramine, by cytochrome P450 2D6.2 (CYP2D6.2), CYP2D6.10A, CYP2D6.10C, and P34S, G42R, R296C, and S486T mutants expressed in recombinant Saccharomyces cerevisiae were compared with those by CYP2D6.1 (wild-type) in order to clarify the effects of genetic polymorphism of CYP2D6 on the metabolism of neuroactive steroids and amines in the brain. For the 6β-hydroxylation of progesterone, the V max values for CYP2D6.2, CYP2D6.10A, and the P34S and G42R mutants, were less than half of those for CYP2D6.1, and CYP2D6.10C had a higher K m and a lower V max than the wild-type. The V max/K m values for CYP2D6.10A, CYP2D6.10C, and the P34S and G42R mutants were 12-31% of that for CYP2D6. The 16α-hydroxylation and 21-hydroxylation of progesterone by CYP2D6.10A, CYP2D6.10C, and the P34S and G42R mutants were not detected, and the R296C mutant had a higher K m for the 16α-hydroxylation and a lower V max for the 21-hydroxylation than those for CYP2D6.1. For dopamine formation from p-tyramine, the K m values for CYP2D6.2 and the R296C mutant were higher than those for CYP2D6.1, CYP2D6.10A, and CYP2D6.10C had a higher K m and a lower V max than the wild-type. The V max/K m values for CYP2D6.2, CYP2D6.10A, CYP2D6.10C and the P34S, G42R and R296C mutants were less than 45% of those for the wild-type. These results suggest the possibility that the polymorphism of CYP2D6, including CYP2D6*2, CYP2D6*10 and CYP2D6*12, might affect an individual behavior and the central nervous system through endogenous compounds, such as neuroactive steroids and tyramine, in the brain.

Original languageEnglish
Pages (from-to)117-123
Number of pages7
JournalMolecular Brain Research
Volume129
Issue number1-2
DOIs
Publication statusPublished - Oct 22 2004

Keywords

  • CYP2D6
  • Dopamine formation from p-tyramine
  • Human brain
  • Polymorphism
  • Progesterone hydroxylation

ASJC Scopus subject areas

  • Molecular Biology
  • Cellular and Molecular Neuroscience

Fingerprint Dive into the research topics of 'Effect of genetic polymorphism on the metabolism of endogenous neuroactive substances, progesterone and p-tyramine, catalyzed by CYP2D6'. Together they form a unique fingerprint.

  • Cite this