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

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

doi:10.1016/0006-2952(81)90125-8

Cited by 95 publications

(24 citation statements)

References 18 publications

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“…This was confirmed by experiments performed with liver microsomes from rats treated with troleandomycin, another strong inducer of P450s 3A. In the troleandomycin-treated rat microsomes, a large part of P450 3A exists as an inactive P450-Fe(II)-nitrosoalkane complex that is formed in vivo (Pessayre et al, 1981;Delaforge et al, 1983;Pershing and Franklin, 1982). P450 3A is easily regenerated as an active form by treatment of microsomes with ferricyanide which dissociates the P450-nitrosoalkane complex.…”

Section: Interaction Of Ergot Derivatives With Rat Liver P450smentioning

confidence: 79%

High affinity of ergopeptides for cytochromes P450 3A

Peyronneau

Delaforge

Riviere³

et al. 1994

European Journal of Biochemistry

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The interaction between rat and human liver cytochromes P450 with a series of lysergic acid derivatives and ergopeptide alkaloids was studied by difference visible spectroscopy. Ergopeptides, like bromocriptine, ergocryptine and dihydroergotamine, strongly interacted with rat liver microsomes with the appearance of a difference spectrum which is characteristic of their binding to a protein site close to the heme. The intensity of this spectrum was clearly dependent on the amounts of P450s 3A in the microsomes and was at its maximum in dexamethasone-treated rat microsomes. All the ergopeptides studied exhibited a high affinity for rat P450s 3A (K-around 1 pM), although lysergic acid derivatives not bearing the tripeptide moiety failed to give significant interactions with these P450s. A cyclic azatripeptide exhibiting a structure very similar to that of the tripeptide moiety of ergopeptides also interacted with P450s 3A with appearance of an intense type I difference spectrum. Very similar results were observed with two allelic forms of human liver P450 3A4, P450 NF25 and P450 hPCN1, produced in yeast. In both cases all the ergopeptides studied showed high affinities for the P450s (K? 0.6-2.2 pM) and an intense shift from the low-spin to the high-spin state upon substrate binding (60-100% spin shift). Lysergic acid derivatives not bearing the tripeptide group of ergopeptides also completely failed to interact with P450s 3A4.Liver microsomes from rats pretreated with dexamethasone, a specific inducer of P450 3A, were found to be particularly active for the hydroxylation of bromocriptine, which occurs at the level of its tripeptide moiety. Human liver microsomes as well as P450 NF25 and P450 hPCNl also exhibited a high activity for bromocriptine hydroxylation at this level.These results show that ergopeptides exhibit a particularly high affinity for P450s of the 3A subfamily. The tripeptide moiety of ergopeptides is essential for their recognition by P450s 3A and binds at a site close to P450 heme, producing type-I difference spectra. Accordingly, at least one of the studied ergopeptides, bromocriptine, is hydroxylated by P450s 3A at the proline ring of the cyclopeptide moiety. As cyclosporine is known to be a good substrate of P450s 3A, these results suggest that P450s 3A may be especially prone in a general manner to recognize and oxidize peptides or pseudopeptides.Cytochrome P450 enzymes constitute a superfamily of heme-thiolate proteins that catalyse the primary oxidation of a wide variety of natural endogenous substrates like steroids, fatty acids, prostaglandins, leukotrienes and lipid hydroperoxides. They also play an important role in the metabolism of exogenous compounds like drugs, procarcinogens, solvents, anesthetics and environmental pollutants. Their broad substrate specificity is now well understood on the basis of enzyme multiplicity (Gonzalez, 1992). More than 220 P450s have been sequenced and characterized; they have been classified on the basis of primary amino acid sequence similarity (Nelson et...

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Section: Interaction Of Ergot Derivatives With Rat Liver P450smentioning

confidence: 79%

High affinity of ergopeptides for cytochromes P450 3A

Peyronneau

Delaforge

Riviere³

et al. 1994

European Journal of Biochemistry

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“…In the 1970s, Ndealkylation of the prototypical tertiary alkylamine P450 inhibitor SKF 525-A (Proadifen) to yield the secondary alkylamine was established as a first step toward generating the metabolite capable of binding with heme to yield the MI complex detected by a Soret absorbance peak at 455 nm (Schenkman et al, 1972). In addition, N-dealkylation of the tertiary alkylamine macrolide antibiotics troleandomycin and erythromycin was demonstrated as the initial step in their MI complex-based inactivation of CYP3A4 (Danan et al, 1981;Pessayre et al, 1981Pessayre et al, , 1982. These findings illustrate the importance of secondary alkylamines in mechanistic considerations for MI complexbased P450 inactivation for tertiary alkylamines as well as for the secondary alkylamines themselves.…”

Section: Discussionmentioning

confidence: 99%

Metabolism-Dependent Inhibition of CYP3A4 by Lapatinib: Evidence for Formation of a Metabolic Intermediate Complex with a Nitroso/Oxime Metabolite Formed via a Nitrone Intermediate

et al. 2013

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Metabolism-dependent inhibition (MDI) of cytochrome P450 (P450) enzymes has the potential to cause clinically relevant drug-drug interactions. In the case of several alkylamine drugs, MDI of P450 involves formation of a metabolite that binds quasi-irreversibly to the ferrous heme iron to form a metabolic intermediate (MI) complex. The specific metabolites coordinately bound to ferrous iron and the pathways leading to MI complex formation are the subject of debate. We describe an approach combining heme iron oxidation with potassium ferricyanide and metabolite profiling to probe the mechanism of MI complex-based CYP3A4 inactivation by the secondary alkylamine drug lapatinib. Ten metabolites formed from lapatinib by CYP3A4-mediated heteroatom dealkylation, Chydroxylation, N-oxygenation with or without further oxidation, or a combination thereof, were detected by accurate mass spectrometry. The abundance of one metabolite, the N-dealkylated nitroso/ oxime lapatinib metabolite (M9), correlated directly with the prevalence or the disruption of the MI complex with CYP3A4. Nitroso/ oxime metabolite formation from secondary alkylamines has been proposed to occur through two possible pathways: (1) sequential N-dealkylation, N-hydroxylation, and dehydrogenation (primary hydroxylamine pathway) or (2) N-hydroxylation with dehydrogenation to yield a nitrone followed by N-dealkylation (secondary hydroxylamine pathway). All intermediates for the secondary hydroxylamine pathway were detected but the primary N-hydroxylamine intermediate of the primary hydroxylamine pathway was not. Our findings support the mechanism of lapatinib CYP3A4 inactivation as MI complex formation with the nitroso metabolite formed through the secondary hydroxylamine and nitrone pathway, rather than by N-dealkylation to the primary amine followed by N-hydroxylation and dehydrogenation as is usually assumed.

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“…Three additional macrolide antibiotics, josamycin, midecamycin, and spiramycin, do not form cytochrome P-450 MI complexes (4,13). Cytochrome P-450 MI complex formation by erythromycin and troleandomycin results in the formation of a metabolically inactive cytochrome P-450 species (3,11). Furthermore, administration of these macrolide antibiotics results in clinical pharmacokinetic interactions with steroids (8), theophylline (2), and cyclosporin (5).…”

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“…The assay of cytochrome P-450 3A in human hepatic microsomal samples was accomplished by immunoquantitation as previously reported (17). RESULTS The possibility of hepatic cytochrome P-450 MI complex formation by dirithromycin in microsomes from untreated, phenobarbital-pretreated, and dexamethasone-pretreated rats was investigated on the basis of the observation that some macrolide antibiotics cause cytochrome P-450 MI complex formation as evidenced by a 456-nm absorption peak in hepatic microsomes (9,11). Troleandomycin readily formed a cytochrome P-450 type I binding spectrum with hepatic microsomes isolated from dexamethasone-pretreated rats and to a lesser extent with microsomes from phenobarbital-pretreated rats ( (16).…”

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Cytochrome P-450 complex formation by dirithromycin and other macrolides in rat and human livers

Lindstrom

Hanssen

Wrighton

1993

Antimicrob Agents Chemother

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Some macrolide antibiotics cause clinical drug interactions, resulting in altered metabolism of concomitantly administered drugs, via formation of an inactive cytochrome P-450 complex. In the present study, the formation of a cytochrome P-450 type I binding spectrum and a metabolic intermediate complex by troleandomycin and dirithromycin was assessed in liver microsomes obtained from untreated rats and phenobarbital-or dexamethasone-pretreated rats. Troleandomycin produced a type I binding spectrum and metabolic intermediate complex in microsomes from dexamethasone-and phenobarbital-pretreated rats. Dirithromycin did not produce a detectable type I binding spectrum but formed a small cytochrome P-450 metabolic intermediate complex (6% of that formed by troleandomycin) in microsomes from dexamethasonepretreated rats only. The formation of a cytochrome P-450 type I binding spectrum and a metabolic intermediate complex by troleandomycin, erythromycin, dirithromycin, and erythromycylamine was also assessed in microsomes prepared from human livers. Troleandomycin and erythromycin formed a type I binding spectrum and a metabolic intermediate complex which were larger in microsomes from subjects on barbiturate therapy than in microsomes from subjects with no recent barbiturate exposure. Erythromycylamine did not form a detectable type I binding spectrum with any of the human microsomal samples, but a small metabolic intermediate complex was formed with microsomes from a subject on phenobarbital, phenytoin, and propranolol therapy. Dirithromycin did not form a detectable type I binding spectrum or a metabolic intermediate complex in any human liver sample. Preclinical quantitation of the human metabolic intermediate complex may be helpful in predicting the possibility of clinical drug interactions of new drug candidates.A number of classes of xenobiotic compounds such as amphetamines, arylamines, methylenedioxybenzenes, dioxolanes, and hydrazines interact with cytochrome P-450, resulting in the formation of a cytochrome P-450 type I binding spectrum and, subsequent to reduction of the drugenzyme complex with NADPH, a characteristic metabolic intermediate (MI) complex (10). Among those compounds producing cytochrome P-450 MI complexes are the macrolide antibiotics erythromycin, oleandomycin, troleandomycin, clarithromycin, and roxithromycin, although the latter two macrolides are weak formers of cytochrome P-450 MI complexes (13). Three additional macrolide antibiotics, josamycin, midecamycin, and spiramycin, do not form cytochrome P-450 MI complexes (4, 13). Cytochrome P-450 MI complex formation by erythromycin and troleandomycin results in the formation of a metabolically inactive cytochrome P-450 species (3, 11). Furthermore, administration of these macrolide antibiotics results in clinical pharmacokinetic interactions with steroids (8), theophylline (2), and cyclosporin (5). It was, therefore, of interest to determine if dirithromycin, a new macrolide antibiotic, and erythromycylamine, a metabolite of dirithromycin, ...

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

Cited by 95 publications

References 18 publications

High affinity of ergopeptides for cytochromes P450 3A

High affinity of ergopeptides for cytochromes P450 3A

Metabolism-Dependent Inhibition of CYP3A4 by Lapatinib: Evidence for Formation of a Metabolic Intermediate Complex with a Nitroso/Oxime Metabolite Formed via a Nitrone Intermediate

Cytochrome P-450 complex formation by dirithromycin and other macrolides in rat and human livers

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