Elsevier

Biochemical Pharmacology

Volume 30, Issue 6, 15 March 1981, Pages 553-558
Biochemical Pharmacology

Self-induction by triacetyloleandomycin of its own transformation into a metabolite forming a stable 456 nm-absorbing complex with cytochrome P-450

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Abstract

Triacetyloleandomycin (TAO), a macrolide antibiotic containing a tertiary amine function, —N(CH3)2, gave a small type I binding spectrum with, and was slightly demethylated by, musomes from control rats. No detectable 456 nm-absorbing complex was formed in vitro upon incubation of control musomes with TAO and NADPH; no complex formed in vivo could be detected in musomes from rats killed 1 hr after a single dose of TAO, 1 mole/kg i.p. Repeated administration of TAO, 1 mmole/kg i.p. daily for 4 days increased the liver weight/body weight ratio, hepatic musomal protein concentration, NADPH-cytochrome c reductase activity, and the amplitude of the TAO type I binding spectrum but did not change the CO-binding spectrum of dithionite-reduced musomes or the activity of TAO demethylase. musomes isolated from rats treated with repeated doses of TAO exhibited an enormous absorption peak at 456 nm; the absorption at 456 nm was slightly increased upon incubation with TAO and NADPH; the absorption peak at 456 nm disappeared upon treatment of the musomes with 50 μM potassium ferricyanide. After disruption of the complex by potassium ferricyanide, cytochrome P-450 in TAO-treated rats was increased by 260% above that in control musomes; the amplitude of the TAO-type I binding spectrum was increased by 4500% and TAO-demethylase activity was increased by 670%. It is concluded that TAO induces its own transformation into a metabolite which forms a stable complex with the iron (II) of reduced cytochrome P-450.

References (27)

  • S.L. Spector et al.

    J. Allergy clin. Immun.

    (1974)
  • M. Weinberger et al.

    J. Allergy clin. Immun.

    (1977)
  • M.R. Franklin

    Pharmac. Ther.

    (1977)
  • M. Hirata et al.

    Biochem. Pharmac.

    (1979)
  • J.B. Schenkman et al.

    Biochem. Pharmac.

    (1972)
  • J. Werringloer et al.

    Archs. Biochem. Biophys.

    (1975)
  • D. Mansuy

    Biochimie

    (1978)
  • D. Mansuy et al.

    Biochem. Pharmac.

    (1976)
  • D. Pessayre et al.

    Biochem. Pharmac.

    (1981)
  • D. Pessayre et al.

    Biochem. Pharmac.

    (1976)
  • T. Omura et al.

    J. biol. Chem.

    (1964)
  • A.M. Jezequel et al.
  • W. Djaczenko et al.

    Ann. Sclavo

    (1973)
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      While the 455–460 nm peak is usually considered to reflect the interaction of carbene, an uncharged reactive intermediate, with the iron [30]. Therefore, the 455–460 nm peak of type III binding spectrum is thought to reflect the formation of P450 metabolic–intermediate complex [30,32–34]. We observed this novel binding spectrum in the aromatase–DBF complex in the absence of NADPH-P450 reductase and NADPH.

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