Modulation of human flavin-containing monooxygenase 3 activity by tricyclic antidepressants and other agents: Importance of residue 428

Adali O., Carver G., Philpot R.

ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS, cilt.358, sa.1, ss.92-97, 1998 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 358 Sayı: 1
  • Basım Tarihi: 1998
  • Doi Numarası: 10.1006/abbi.1998.0835
  • Dergi Adı: ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Sayfa Sayıları: ss.92-97
  • Anahtar Kelimeler: FMO, FMO3, drug metabolism, imipramine, human, ADULT HUMAN LIVER, ESCHERICHIA-COLI, SUBSTRATE-SPECIFICITY, PRIMARY ALKYLAMINES, MULTIPLE FORMS, GENE FAMILY, AMINES, SULFOXIDATION, OXIDATION, FMO3
  • Orta Doğu Teknik Üniversitesi Adresli: Evet

Özet

Human flavin-containing monooxygenase 3 (FMO3) is subject to modulation by tricyclic antidepressants and other agents. Imipramine activates FMO3-catalyzed metabolism of methimazole at all substrate concentrations tested. This distinguishes FMO3 from rabbit FMO1 and FMO2, which are activated at high substrate concentration and inhibited at low substrate concentration, and pig FMO1, which is inhibited at all substrate concentrations. The response of FMO3 is also unique in that chlorpromazine is markedly more effective as a modulator than is imipramine. n-Octylamine,MgCl2, and HgCl2 all inhibit FMO3, the frst two in a biphasic manner. Substitution of lysine for threonine at position 428 significantly alters the response of FMO3 to modulators without changing the kinetic parameters for the metabolism of the substrate. Activation by imipramine and chlorpromazine is reduced or abolished and inhibition, most obvious at low substrate concentrations, is observed. This is consistent with elimination of self-activation in the metabolism of imipramine. The mutation at 428 also eliminates the biphasic nature of the inhibition by n-octylamine and MgCl2, but does not alter the effect of HgCl2. Our findings show that the activity of FMO3 can be modulated by large drug molecules as well as short-chain amines and metal ions. This modulation can be markedly altered by changing a single amino acid in the enzyme. (C) 1998 Academic Press.