Portal de Periódicos da CAPES

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

1981; Elsevier BV; Volume: 30; Issue: 6 Linguagem: Inglês

10.1016/0006-2952(81)90125-8

1873-2968

Dominique Pessayre, Véronique Descatoire, Mitka Konstantinova-Mitcheva, Joâo-Carlos Wandscheer, Barton Cobert, Régine Level, Jean‐Pierre Benhamou, Maryse Jaouen, Daniel Mansuy,

Cancer therapeutics and mechanisms

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.