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D Mansuy

Publications and source records attributed to D Mansuy.

At least 145 records · Page 8Linked to original sources
PubMed1980

13C nuclear magnetic resonance studies of the binding of alkyl isocyanides to soybean leghemoglobin; comparison with animal myoglobins.

13C NMR of labelled alkyl isocyanide ligands has been used with a view to probe the protein environment around the heme site of Soybean leghemoglobin, and comparatively, those of sperm whale myoglobin and monomeric Glycera hemoglobin. The terminal carbon of the isocyanide, which is known to be highly sensitive to change in hybridization of the nitrogen, could be expected to reflect the movement of the alkyl group through steric interactions. Three alkyl isocyanides (alkyl = methyl, ethyl & n-butyl) have therefore been used and the 13C0 chemical shift values were measured for each ligand bound to the various proteins studied. In all cases, the 13C0 resonance of the bound ligand were shifted considerably down-field with respect to those of the free unbound species, but the pattern of these displacements revealed more pronounced steric hindrance in the case of some proteins compared to others. The modifications of the chemical shift values of binding delta delta = delta bound -- delta free) were least in the case of leghemoglobin; moreover, the delta delta values were insensitive to the length of the alkyl chain (methyl to n-butyl) when bound to leghemoglobin, in contrast to the other proteins examined. The results are interpreted as arising from a diminished steric hindrance to isocyanide binding with leghemoglobin, in conformity with the recently published X-ray structure which reports the existence of a large heme pocket on the distal side.

Animals↗
PubMed1980

Spectral characterization of cytochrome P-450 of a strain of Candida tropicalis grown on tetradecane.

Several properties of the cytochrome P-450 induced in the yeast Candida tropicalis by growth on tetradecane have been studied by differential visible spectroscopy on microsomes. The spectral changes typical of this cytochrome have been obtained by subtraction of an unspecific spectral change, possibly due to the presence of other hemoproteins in microsomes, from the experimental difference spectra. Like the previously described cytochromes P-450 from yeast and mammalian liver, C. tropicalis cytochrome P-450 is in spin-state equilibrium at ambient temperature: about 30% of the originally low-spin cytochrome is converted to the high-spin state upon increasing the ionic strength of the medium, whereas 30% of the originally high-spin cytochrome is converted to the low-spin state upon addition of hydrophobic alcohols. C. tropicalis cytochrome P-450 readily binds nitrogenous ligands, isocyanides and phosphines in the ferric and ferrous state with spectral characteristics similar to those reported for other yeast or mammalian cytochromes P-450. It also reacts sucessively with cumylhydroperoxide and 1,3-benzodioxole to form a high-valent iron-oxo species and an iron-carbene metabolite complex. However it fails to produce any spectral or spin-state change upon addition of hydrophobic non-coordinating compounds such as n-tetradecane, its substrate in vivo.

Alkanes↗
PubMed1980

[P-450 cytochromes and mono-oxygenases. Mechanism of action. Consequences in pharmacology and toxicology (author's transl)].

The mechanism of action of mono-oxygenases of the biotransformation system of exogenic compounds is described emphasising two characteristics which are at the root of the implications of this system in pharmacology and toxicology : its non-specificity with regard to substrates and its great chemical reactivity. The consequences of the biotransformation of a drug (modulation of its therapeutic effect, appearance of noxious side-effects due to the formation of reactive metabolites) are illustrated by a few examples. Finally, the various mechanisms by which a drug may modify biotransformation and the effects of a second drug given in association, are analysed.

Animals↗
PubMed1979

Biotransformation of chloroform by rat and human liver microsomes; in vitro effect on some enzyme activities and mechanism of irreversible binding to macromolecules.

The effects of chloroform on some rat microsomal enzyme activities were studied in vitro. Maximum inhibition of oxygen consumption, NADPH oxidase and NADPH-cytochrome c reductase was observed at 0.5 mM chloroform; prior metabolization of CHCl3 by microsomal monooxygenases increased inhibition by about 50% at 0.2-0.5 mM chloroform. Higher concentrations produced a paradoxical reversal of inhibition, whereas p-nitroanisole demethylase was steadily inhibited by about 50% up to 10 mM chloroform. Irreversible binding of 14CHCl3 was confirmed to depend on chloroform metabolization by monooxygenases. The increased irreversible binding due to phenobarbital induction is accompanied by a diminished affinity towards chloroform as shown by increased KM of irreversible binding, and a higher spectral dissociation constant KS. Aminoacids with nucleophilic functions (histidine, cysteine) partially prevented the irreversible binding of chloroform metabolites to microsomes; non-volatile radioactive derivatives were recovered in trichloracetic acid supernatants when microsomes were incubated with cysteine, but not with histidine. Phosgene has been demonstrated as a biological metabolite of chloroform: its possible reactions with nucleophilic groups of macromolecules, water and added aminoacids partly explain these experimental data. Similar results were obtained with human microsomes, showing that chloroform hepatotoxicity in man could involve the same mechanisms.

Animals↗
PubMed1979

A class of strong inhibitors of microsomal monooxygenases: the ellipticines.

Ellipticine (E) and its 9-hydroxy derivative inhibit strongly various liver monooxygenase activities mediated by microsomes from control and phenobarbital (PB), benzo[alpha]pyrene (BP) or Aroclor 1254 (Aroclor)-pretreated rats. The inhibition constants, Ki, are remarkably low, and often smaller than 1 micron, particularly in the case of microsomes containing cytochrome P-448. The inhibitory potency (I50) of 9-hydroxyellipticine (9-OHE) is larger (about ten-fold) than the one of classical inhibitors (metyrapone or 7,8-benzoflavone (7,8-BF)), whatever the activities studied and the induction of microsomes. Differences exist between the mechanisms of inhibition according to the form of cytochrome P-450 present in microsomes of differently pretreated rats; whichever the activities studied, one observes: (a) a competitive inhibition towards the activity of non-induced or PB-induced microsomes and (b) a non-competitive inhibition towards the activity of Aroclor or BP-induced microsomes, at variance with 7,8-BF. These results are in good agreement with the interaction properties of the ellipticines with microsomal cytochromes P-450.

Alkaloids↗
PubMed1979

Ellipticines as potent inhibitors of microsomes-dependent chemical mutagenesis.

9-Hydroxyellipticine (9-OHE), an inhibitor of microsomal monooxygenase activities has been shown to exert a large or even complete decrease of the mutagenicity, on the Salmonella strains of a great number of compounds (aromatic amines, polycyclic aromatic hydrocarbons, fungal toxins, azo compounds, tobacco smoke condensate). 9-OHE and 9-fluoroellipticine are more potent inhibitors than ellipticine itself. The inhibitions exerted by 9-OHE are not even equalled by 10-fold higher doses of 7,8-benzoflavone (7,8-BF). There is a good correlation between these data and the interaction properties of ellipticines with microsomal cytochromes P-450.

Alkaloids↗
PubMed1978

Formation of complexes between microsomal cytochrome P-450-Fe(II) and nitrosoarenes obtained by oxidation of arylhydroxylamines or reduction of nitroarenes in situ.

A cytochrome P-450 complex exhibiting a Soret peak at 454 nm is formed by direct interaction of nitrosobenzene with NADPH-reduced rat liver microsomes in anaerobic conditions, by reaction of phenylhydroxylamine with aerobic microsomes or during nitrobenzene reduction by NADPH-reduced or dithionite-reduced microsomes. In the latter conditions, the complex formation is only transient as it is unstable to dithionite. Analogous reactions with myoglobin lead to the previously described myoglobin-Fe(II)-nitrosobenzene complex which has similar properties to those of the 454-nm-absorbing cytochrome P-450 complex. This analogy, together with the various conditions of its formation, strongly indicates that it is a cytochrome-P-450-Fe(II)-nitrosobenzene complex. The corresponding complex with the 4-chloro-nitrosobenzene ligand is formed in similar conditions. Cytochrome P-450-Fe(II) complexes with nitrosoarenes seem less stable than the previously described complexes with nitrosoalkanes.

Animals↗