Inhibition and induction of cytochrome P450 isozymes after repetitive administration of imipramine in rats

Y. Masubuchi, C. Takahashii, N. Fujio, T. Horie, T. Suzuki, S. Imaoka, Y. Funae, S. Narimatsu

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

Repetitive oral administration of imipramine (100 mg/kg/day for 5 days) caused a decrease in rat liver microsomal debrisoquine 4-hydroxylase activity, a characteristic reaction catalyzed by cytochrome P450 (CYP) 2D1. Other CYP2D-dependent reactions (such as bunitrolol 4-hydroxylation, lidocaine 3-hydroxylation, and propranolol 4-, 5- and 7-hydroxylations) were also impaired by the treatment, but not those catalyzed by other CYP isozymes. Imipramine pretreatment did not change the immunochemically determined content of the CYP2D protein, suggesting that CYP2D is inactivated. Imipramine pretreatment also resulted in an increase in total CYP content and in formation of a ferrous CYP metabolic intermediate (MI)- complex absorbing at 454 nm. Although the total CYP content was increased by the treatment of these microsomes with ferricyanide to dissociate the MI- complex, the CYP2D-dependent activities were not restored, suggesting that the MI-complex was not the primary cause of CYP2D inhibition. This pretreatment regimen caused marked increases in immunochemically determined levels of CYP2A1, CYP2B1, CYP2B2, CYP2C6, and CYP3A2, and in the activities of 2α-, 2β-, 6β-, 7α-, 16α-, and 16β-hydroxylation and 17-oxidation of testosterone. These results indicate that imipramine has two actions on the liver CYP system (i.e. as an inhibitor of the CYP2D enzyme and as a phenobarbital-type inducer).

Original languageEnglish
Pages (from-to)999-1003
Number of pages5
JournalDrug Metabolism and Disposition
Volume23
Issue number9
Publication statusPublished - 1995
Externally publishedYes

Fingerprint

Imipramine
Cytochrome P-450 Enzyme System
Isoenzymes
Rats
Hydroxylation
Liver
Cytochrome P-450 CYP2B1
Cytochrome P-450 CYP2D6
Enzyme Inhibitors
Phenobarbital
Microsomes
Lidocaine
Propranolol
Oral Administration
Testosterone
Oxidation
Therapeutics
Proteins

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology

Cite this

Masubuchi, Y., Takahashii, C., Fujio, N., Horie, T., Suzuki, T., Imaoka, S., ... Narimatsu, S. (1995). Inhibition and induction of cytochrome P450 isozymes after repetitive administration of imipramine in rats. Drug Metabolism and Disposition, 23(9), 999-1003.

Inhibition and induction of cytochrome P450 isozymes after repetitive administration of imipramine in rats. / Masubuchi, Y.; Takahashii, C.; Fujio, N.; Horie, T.; Suzuki, T.; Imaoka, S.; Funae, Y.; Narimatsu, S.

In: Drug Metabolism and Disposition, Vol. 23, No. 9, 1995, p. 999-1003.

Research output: Contribution to journalArticle

Masubuchi, Y, Takahashii, C, Fujio, N, Horie, T, Suzuki, T, Imaoka, S, Funae, Y & Narimatsu, S 1995, 'Inhibition and induction of cytochrome P450 isozymes after repetitive administration of imipramine in rats', Drug Metabolism and Disposition, vol. 23, no. 9, pp. 999-1003.
Masubuchi Y, Takahashii C, Fujio N, Horie T, Suzuki T, Imaoka S et al. Inhibition and induction of cytochrome P450 isozymes after repetitive administration of imipramine in rats. Drug Metabolism and Disposition. 1995;23(9):999-1003.
Masubuchi, Y. ; Takahashii, C. ; Fujio, N. ; Horie, T. ; Suzuki, T. ; Imaoka, S. ; Funae, Y. ; Narimatsu, S. / Inhibition and induction of cytochrome P450 isozymes after repetitive administration of imipramine in rats. In: Drug Metabolism and Disposition. 1995 ; Vol. 23, No. 9. pp. 999-1003.
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