Steric effect on the M site of nanolaminate compounds M(2)SnC (M = Ti, Zr, Hf and Nb).

In this paper we report calculations based on an all electron ab initio full-potential linearized augmented plane-wave method using the generalized gradient approximation within the density functional theory to determine the structures of Ti(2)SnC, Zr(2)SnC, Hf(2)SnC and Nb(2)SnC. The lattice constants obtained after geometry optimization are in good agreement with experimental data. It is observed from these results that there exists a steric effect on the M site. For M atoms with atomic radius (Zr, Hf) larger than that of tin, the polyhedra (octahedron and trigonal prism) constituting the unit cell are less distorted compared to those related to M atoms with atomic radius (Ti, Nb) similar to that of tin. The computed values for the bulk modulus of these ternary carbides are predicted to be about 69% of those of the corresponding binary carbides MC. The analysis of the projected local density of states shows that the major hybrids come from M (M = Ti, Zr, Hf, Nb) d and C p states.

HRTEM and EELS study of Y2O3/MgO thin films.

Y2O3 thin films deposited on (001)-MgO substrate have been investigated by high-resolution transmission electron microscopy (HRTEM) and electron energy loss spectroscopy. Digital processing of the HRTEM images reveals the presence of grains with a crystallographic structure different from that of the rest of the film (Ia3). The spectrum imaging technique has been applied in vicinity of the Y2O3/MgO interface to get a better knowledge of the phases nucleated on the substrate surface. Fine structures of the O K-edge have been studied in detail; actually two kinds of spectra have been detected in the yttrium oxide thin film. These spectra have been compared to self-consistent full multiple scattering calculations (SC-FMS). One family of spectra has then been associated to the well-known Ia3 structure. The other family of spectra has been compared to calculations performed for the other known structures (such as hexagonal or monoclinic) of Y2O3 with a little success. We have finally compared these spectra to calculations performed with a particular atomic arrangement (octahedral) of Y and O atoms, which leads to a good match between experimental and calculated spectra. Our results emphasize the benefit of coupling several techniques such as HRTEM, EELS and SC-FMS for the determination of structures at the nanometric scale.

Dual effects of macrolide antibiotics on rat liver cytochrome P-450. Induction and formation of metabolite-complexes: a structure-activity relationship.

Previous studies have shown that the macrolide antibiotics, troleandomycin and erythromycin, are able to induce their own transformation into a metabolite forming an inactivated complex with rat liver cytochrome P-450. This paper reports the results of a study on the effects of several macrolide antibiotics including oleandomycin, erythromycin derivatives, josamycin, methymycin, tylosin, spiramycin and rifampicin, as well as antibiotics of other series, such as tetracycline and lincomycin, on rat liver cytochromes P-450 in vivo and in vitro. Only the antibiotics containing the desosamine and mycaminose amino sugars were able to give the dual effects already found with troleandomycin: induction of cytochrome p-450 and formation of an inhibitory cytochrome P-450--iron--nitrosoalkane metabolite complex in vivo or in vitro. From these studies, it appears that two structural factors are important for a macrolide antibiotic to lead to such effects: the presence of a non-hindered readily accessible N-dimethylamino group and the hydrophobic character of the molecule. These data are discussed in relation to the adverse effects observed during drug associations involving some of these macrolide antibiotics.

Metabolic hydroxylation of the thiophene ring: isolation of 5-hydroxy-tienilic acid as the major urinary metabolite of tienilic acid in man and rat.

The metabolism of tienilic acid, a drug containing a thiophene ring, was reinvestigated in man, rat and dog. The major urinary metabolite in man and rat was isolated and completely characterized by comparison with a synthetic compound. This metabolite derives from the hydroxylation of the thiophene ring of tienilic acid in position 5. Its isomers, 3- and 4-hydroxy-tienilic acids, were synthetized but could be detected neither in man nor in rat urine. Because of its particular behaviour toward electrophiles, 5-hydroxy-tienilic acid was found to react with diazomethane with the formation of a complex mixture of methylated products. This made difficult its measurement by a previously described GLC technique, after acidic extraction and methylation by diazomethane. A new very simple assay using HPLC and direct injection of urine is described in this paper. This assay led to a very precise and reproductible determination of tienilic acid and its hydroxylated metabolite in urine. Up to 50% of tienilic acid is excreted in man or rat urine as 5-hydroxy-tienilic acid whereas this metabolite does not appear in dog urine. These data describe the first example of metabolic hydroxylation of the thiophene ring.

Recognition and oxidative metabolism of cyclodipeptides by hepatic cytochrome P450.

Possible recognition of peptide derivatives by hepatic cytochrome P450 3A has been suggested by binding and metabolism of numerous pseudopeptidic compounds such as ergot derivatives and cyclosporin. Natural linear or cyclic dipeptides containing hydrophobic amino acids produced by microorganisms and present in mammals are able to interact with the P450 active site through either iron-amine interactions (Type II) or hydrophobic Type I interactions. P450 3A from dexamethasone-treated rats or yeast-expressed P450 human 3A4 are the most potent in such interactions, which are particularly strong with peptides containing a histidyl residue. Some cyclodipeptides are rapidly transformed by rat cytochrome P450 3A to mono- or dihydroxylated metabolites, with turnovers around 3 nmoles min(-1) P450(-1). Linear peptides are poorly transformed in these conditions. This metabolism of cyclodipeptides occurs in 8 species including man. Such interactions and metabolism have only minor consequences in terms of P450 3A binding and metabolism of classical P450 3A substrates. These data reinforce the concept that, in addition to their effect on the regulation of P450 neosynthesis, naturally occurring endogenous peptides are also substrates of P450 3A. The physiological activities of these peptides may be modulated by their metabolism.

pH effects on the N-demethylation and formation of the cytochrome P-450 iron II nitrosoalkane complex for erythromycin derivatives.

The effects of pH on access to the cytochrome P-450 active site, N-demethylation and formation of the cytochrome P-450 Fe(II)-RNO metabolite complex for a series of erythromycin derivatives were examined. Studies were performed with dexamethasone-treated rat liver microsomes containing large amounts of cytochrome P-450 3A isozymes. In addition to factors such as hydrophobicity or hindrance around the dimethyl-amino function, the ionisation state of the N(CH3)2 group played an important role in the recognition and metabolism of the substrate by cytochrome P-450. Esterification of the desosamine in the beta position of the N(CH3)2 group leads to lower pKa values for the R--N+ H(CH3)2 <--> [R--N (CH3)2] + H+ equilibrium. At physiological pH, the amine group is mainly in the unprotonated form. Consequently, easier access to the protein active site and significant formation of cytochrome P-450 Fe(II)-RNO metabolite complex are observed for these derivatives. These results led us to interpret the formation of cytochrome P-450 Fe(II)-RNO metabolite complex as a series of multiple steps equilibria depending on the ionisation state of the N(CH3)2 group, the partition coefficient of the substrate between the microsomal layer and the aqueous media and a series of metabolic reactions leading partially to the final inhibitory nitrosoalkane-cytochrome P-450 Fe(II) complex.

Study of the local atomic strain field in a Zr-doped TiAl intermetallic alloy by EXAFS and ab initio FLAPW calculations.

The mechanical properties of gamma-TiAl-based intermetallic alloys are strongly influenced by Ti d-Ti d and Al p-Ti d hybridizations. These directional bonds supply good mechanical properties at high temperature but they are also associated with a low ductility at room temperature. Small amounts (about 3%) of additional elements can improve this behaviour noticeably and modify the mechanical properties. In the present case, the addition of zirconium in the gamma-TiAl-based alloys has been reported to increase their ductility at low temperature. Beyond the modifications of the directional bonds which come directly from the band structure, the different atomic volumes of the solute atoms induce local deformation fields which interact with the dislocations. We present ab initio calculations (FLAPW method) compared with an EXAFS study which the aim is to determine the site preference of zirconium in the TiAl lattice and the deformation fields around the solute atoms.

Drug interactions with macrolide antibiotics: specificity of pseudo-suicide inhibition and induction of cytochrome P-450.

Macrolide antibiotics like Erythromycin and Tri-acetyl oleandomycin (TAO) are metabolized to nitrosoderivatives which cause inactivation of Cytochrome P-450 by forming stable complex with the Iron of the hemoporphyrin. Several derivatives of erythromycin having lost their cladinose moiety are stronger inducer of liver cytochrome P-450 itself. The major form of cytochrome P-450 induced by all these macrolides in rat liver electrophoretically and immunologically indistinguishable from the major form induced by pregnenolone 16 alpha carbonitrile (PCN). This form is particularly able to metabolize macrolide and to lead to the corresponding 456 nm absorbing cytochrome P-450 complexes in vivo and in vitro.

Inhibitory metabolite complex formation of methylenedioxymethamphetamine with rat and human cytochrome P450. Particular involvement of CYP 2D.

Methylenedioxymethamphetamine (MDMA or ecstasy) is a common recreational drug used at rave parties. Unfortunately, MDMA may have neurological effects and in some cases causes hepatotoxicity. MDMA binds to cytochrome P450 in rat and human hepatic microsomal preparations. Upon metabolic transformation of either the methylenedioxy or the methylamino function, it forms an inhibitory P450-metabolite complex. This inhibitory complex is formed predominantly with the P450 2D isozymes. This complex formation may account for the clinical toxicity observed upon ingestion of MDMA, particularly with other compounds normally metabolized by P450 2D6.

Experimental evidence of Cr magnetic moments at low temperature in Cr2A(A=Al, Ge)C.

From x-ray magnetic circular dichroism experiments performed at low temperature on Cr2AlC and Cr2GeC thin films, it is evidenced that Cr atoms carry a net magnetic moment in these ternary phases. It is shown that the Cr magnetization of the Al-based compound nearly vanished at 100 K in agreement with what has been recently observed on bulk. X-ray linear dichroism measurements performed at various angles of incidence and temperatures clearly demonstrate the existence of a charge ordering along the c axis of the structure of Cr2AlC. All these experimental observations support, in part, theoretical calculations claiming that Cr dd correlations have to be considered to correctly describe the structure and properties of these Cr-based ternary phases.

Vitamin E derivatives as new potent inhibitors of microsomal lipid peroxidation.

Several synthetic Vitamin E derivatives are strong inhibitors of lipid peroxidation induced in rat liver microsomes either chemically by ferrous ions and ascorbate or enzymatically by NADPH and carbon tetrachloride. The relative activities of these inhibitors are consistent with their intrinsic antioxidant properties, as peroxyl radicals scavengers. Among them, a 3,4-dihydro-6-hydroxy-2H-1-naphtopyran with IC50 around 0.08 microM is one of the most potent yet known inhibitor of lipid peroxidation.

The stimulatory effects of asbestos on NADPH-dependent lipid peroxidation in rat liver microsomes.

Lipid peroxidation in rat liver microsomes induced by asbestos fibres, crocidolite and chrysotile, is greatly increased in the presence of NADPH, leading to malondialdehyde levels comparable with those induced by CCl4, a very strong inducer of lipid peroxidation. This synergic effect only occurs during the first minutes and could be explained by an increase or a regeneration of the ferrous active sites of asbestos by NADPH, which in turn could rapidly be prevented by the adsorption of microsomal proteins on the surface of the fibres. It is not inhibited by superoxide dismutase, catalase and mannitol, indicating that oxygen radicals are not involved in the reaction. It is also not inhibited by desferrioxamine, indicating that it is not due to a release of free iron ions in solution from the fibres. Lipid peroxidation in NADPH-supplemented microsomes is also greatly increased upon addition of magnetite. This could be linked to the presence of ferrous ions in this solid iron oxide, since the ferric oxides haematite and goethite are completely inactive.

[Puttman-Reye syndrome and ekiri. Neuro-anatomical study and attempt at classification]. / Syndrome de Puttman-Reye et elkiri. Etude neuro-anatomique et essai nosologique

The authors report two cases of Puttman Reye syndrome: one, classical, involving a young child with a fatal encephalopathy with visceral fatty infiltration, the other, less typical, not showing any signs of visceral fatty degeneration. Both cases were subjected to complete anatomical examination of the brain, revealing marked cerebral oedema, in localised areas or in a laminar distribution, with degenerative changes in the neurones and slight demyelinisation. The authors, on the basis both on the classical appearances of the first case as well as the atypical features of the second, envisage a clinical, anatomical and biological link between the Puttman-Reye syndrome,. Thai encephalopathy and Ekiri, which they consider to represent a single entity.

Detection of a nitric oxide synthase possibly involved in the regulation of the Rhodococcus sp R312 nitrile hydratase.

Crude homogenates from Rhodococcus sp 312 catalyze the conversion of L-arginine into L-citrulline and NO2-, the usual oxidation product of NO under aerobic conditions. They also catalyze the conversion of N omega-hydroxy-L-arginine (NOHA) into L-citrulline and NO2- with similar rates (10-15 and 100-150 nmol of product.min-1.(mg of protein)-1 respectively for the crude homogenate and for a fraction obtained from ammonium sulfate precipitation). L-citrulline formation is strongly inhibited by classical inhibitors of mammalian nitric oxide synthases (NOSs) such as N omega-methyl-L-arginine (NMA) and thio-L-citrulline (TC). Finally, the lack of inhibitory effects of EGTA, a classical inhibitor of constitutive mammalian NOSs, and the specific immunodetection of a 100 kD protein from Rhodococcus cytosol by an antibody raised against human inducible NOS, is in favor of the presence of a NOS similar to inducible mammalian NOSs in Rhodococcus sp 312. This NOS should be responsible for the NO-dependent inactivation of Rhodococcus Nitrile Hydratase (NHase) in the absence of light; it could regulate the activity of the latter enzyme.

Microsomal lipid peroxidation and oxy-radicals formation are induced by insoluble iron-containing minerals.

Lipid peroxidation, measured by malondialdehyde formation is induced in rat liver microsomes by insoluble iron-containing minerals (pyrite, magnetite, nemalite and an iron ore, minette de Lorraine) which are generally found either in iron mines or as contaminants of asbestos fibers. In spin-trapping studies using DMPO as a spin trap those minerals are also found to catalyze the oxidation of formate to carboxylate radicals by oxygen, via the formation of hydroxyl radicals. The two processes are mainly due to the presence of redox active iron at the surface of the solid particles and thus are greatly inhibited by desferrioxamine, a strong iron chelator. However, these reactions are not correlated.

In vivo effects of immunostimulating lipopeptides on mouse liver microsomal cytochromes P-450 and on paracetamol-induced toxicity.

Immunomodulating lipopeptides lauroyl-L-Ala-gamma-D-Glu-LL-A2pmNH2-Gly (RP 44.102) and lauroyl-L-Ala-gamma-D-Glu-LL-A2pmNH2 (RP 56.142) were found to protect mice against the hepatotoxicity of paracetamol, which is due to cytochrome P-450 dependent formation of toxic metabolites and radicals. In fact they decreased the amount of hepatic microsomal cytochrome P-450, and the level of CCl4-induced lipid peroxidation. In contrast lauroyl-L-Ala-gamma-D-Glu-DD-A2pmNH2 (RP 53.204), which only differs by the configuration of the two chiral carbons of A2pm (diaminopimelic acid) and is not an immunomodulating agent, failed to protect against poisoning by paracetamol and had no effect on the level of hepatic cytochrome P-450 or the microsomal CCl4-induced lipid peroxidation. This provides a clear connection between the immunostimulating properties of a compound and its effects on xenobiotic biotransformations.