Biol. Pharm. Bull. 28(4) 634—640 (2005)

نویسندگان

  • Takashi ISOBE
  • Hiroyuki HICHIYA
  • Nobumitsu HANIOKA
  • Shigeo YAMAMOTO
  • Sumio SHINODA
  • Yoshihiko FUNAE
  • Tetsuo SATOH
  • Shigeru YAMANO
  • Shizuo NARIMATSU
چکیده

tidepressants that are widely used clinically. As shown in Fig. 1, IMI is oxidized by cytochrome P450 (CYP) mainly via two pathways: side-chain N-demethylation and aromatic ring 2-hydroxylation, forming DMI and 2-hydroxyimipramine (2OH-IMI), respectively. DMI and 2-OH-IMI further undergo 2-hydroxylation and N-demethylation, respectively, forming 2-hydroxy-DMI as the common metabolite (Fig. 1). In the human liver, CYP2D6 is mainly responsible for IMI 2-hydroxylation whereas CYP2C19 and CYP1A2 are involved in N-demethylation. It has been reported that repeated administration of IMI to rats changed hepatic CYP-dependent monooxygenase activities. We have also found that repetitive oral administration of IMI to rats caused a decrease in hepatic microsomal CYP2D-dependent reactions such as debrisoquine 4-hydroxylation, bunitrolol 4-hydroxylation, lidocaine 3-hydroxylation and propranolol 4-, 5and 7-hydroxylations. We have proposed that binding of a reactive metabolite of IMI to rat CYP2D enzyme(s) resulted in the decreased enzyme activities. As a possible mechanism, we speculated that an epoxy metabolite of IMI (1,2or 2,3-epoxide) was involved in the inactivation of rat CYP2D enzyme(s). If the epoxy metabolite(s) of IMI are responsible for the inactivation, DMI would also inactivate the rat CYP2D enzyme(s). Because several CYP2D enzymes are known to be expressed in the rat liver, it is interesting to know what kind of CYP2D isoenzyme(s) are inhibited by IMI or DMI. Furthermore, there is a possibility that CYP2D6, a human functional CYP2D enzyme, is also inactivated by IMI and DMI in a similar manner. The present study was thus conducted to examine these possibilities using radiolabeled and unlabeled DMI and recombinant human and rat CYP2D enzymes.

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تاریخ انتشار 2005