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Biomedical subjects

M Delaforge

Publications and source records attributed to M Delaforge.

At least 73 records · Page 4Linked to original sources
PubMed1986

In vivo formation of sigma-methyl- and sigma-phenyl-ferric complexes of hemoglobin and liver-cytochrome P-450 upon treatment of rats with methyl- and phenylhydrazine.

Ferric sigma-phenyl complexes of hemoglobin and liver cytochrome P-450 are formed in vivo upon administration of C6H5NHNH2 to rats. Small amounts of the sigma-methyl complex of hemoglobin were also detected in vivo upon treatment of rats with CH3NHNH2. At the doses used for CH3NHNH2 (25 and 50 mg/kg) the states and levels of hemoglobin in the blood and spleen, and of cytochrome P-450 in the liver were almost unchanged. On the contrary, C6H5NHNH2 (25-100 mg/kg) led to a decrease of the HbO2 blood level (10-50%), together with an increase in the HbFe(III) level and the appearance of the HbFe(III)-C6H5 complex. The concentration of this complex reaches its maximum value (2 mM) 1 h after C6H5NHNH2 administration (20% of total hemoglobin). At the same time large amounts of HbO2, HbFe(III) and HbFe(III)-C6H5 appeared in the spleen, and remained high up to 24 h after treatment. Treatment of rats with C6H5NHNH2 (25-100 mg/kg) led to a significant decrease in the level of liver cytochrome P-450 (a 70% decrease 2 h after treatment with 100 mg/kg C6H5NHNH2). About 15% of the remaining cytochrome P-450 existed as a cyt.-P-450-Fe(III)-C6H5 complex, a new example of cytochrome P-450-Fe-metabolite complex which is stable in vivo.

Animals↗
PubMed1986

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.

Animals↗
PubMed1985

Some erythromycin derivatives are strong inducers in rats of a cytochrome P-450 very similar to that induced by 16 alpha-pregnenolone carbonitrile.

Erythromycin derivatives having lost the cladinose moiety, erythralosamine and its mono- and diacetate, are strong inducers of liver cytochrome P-450, better than troleandomycin, in rats. The major cytochrome P-450 form induced by all these macrolides is electrophoretically and immunologically indistinguishable from the major form induced in rats by pregnenolone carbonitrile. This form is particularly able to metabolize the macrolides and to lead to the corresponding 456 nm absorbing cytochrome P-450 metabolite complexes in vivo and in vitro.

Animals↗
PubMed1985

Spin state studies on cytochrome P-450 in liver microsomes from obese and diabetic animals.

The spin state of liver microsomal cytochrome P-450 from obese mice and streptozotocin-diabetic mice and rats has been studied both by the temperature and the type I substrates-induced spectral changes. The high spin cytochrome P-450 is significantly decreased in these animals. Moreover absolute spectra indicate that low spin cytochrome P-450 is stabilized in streptozotocin induced-diabetic animals. Thus the physiopathological state may modify the in vivo spin state of cytochrome P-450 and modifications of the microsomal fatty acid composition might contribute to these changes.

Animals↗
PubMed1985

Interactions of safrole and isosafrole and their metabolites with cytochromes P-450.

The structural features which determine interaction of safrole and related methylenedioxyphenyl compounds with cytochromes P-450 or P-448, and determine the induction of these two classes of the cytochrome, have been studied. All methylenedioxyphenyl compounds studied interact with both cytochromes P-450 and P-448 eliciting type I spectral changes and it has been found that the allyl 4-substituent is important in these interactions. Methylenedioxyphenyl compounds with an oxidised allyl 4-substituent exhibited higher affinity for cytochrome P-448 while those possessing an intact allyl or methylvinyl group generally showed higher affinity for cytochrome P-450. Compounds possessing intact allyl and methylenedioxyphenyl groups (safrole, isosafrole and myristicine) were the most potent inducers of cytochromes P-450 and P-448; compounds containing an intact allyl group only (estragole, allybenzene and eugenol methyl ether) or an oxidized allyl group and an intact methylenedioxyphenyl group (epoxysafrole) were inducers of P-448 only.

Animals↗
PubMed1985

Ligand-complex formation between cytochromes P-450 and P-448 and methylenedioxyphenyl compounds.

The formation of ligand complexes between hepatic microsomal cytochrome P-450 and safrole, isosafrole and other methylenedioxyphenyl compounds was studied in vivo and in vitro in rats pretreated with either phenobarbital or 3-methylcholanthrene. Both the phenobarbital-induced cytochrome P-450 and the 3-methylcholanthrene-induced cytochrome P-448 metabolically convert safrole, isosafrole, and those metabolites possessing an intact methylenedioxy group, to reactive metabolites which then interact with the cytochromes to form ligand complexes. Formation of these ligand complexes was accompanied by loss of mixed-function oxidase activities, and dissociation of the complexes with the type I substrate biphenyl restored activities. Safrole and, to a lesser extent, 1'-hydroxysafrole formed complexes in vivo when administered to phenobarbital-pretreated rats; none was obtained with epoxysafrole. However, when administered to 3-methylcholanthrene-pretreated animals all three compounds formed complexes, safrole being the least effective. Epoxysafrole and 1'-hydroxysafrole administered to phenobarbital-pretreated rats resulted in slight inhibition of the type I binding of safrole to liver microsomal P-450 in vitro; in contrast, with 3-methylcholanthrene-pretreated animals marked competitive inhibition was observed. This study shows that oxidation of the allyl chain of safrole analogues enhances their affinity for cytochrome P-448, but not for cytochrome P-450, and further demonstrates that these cytochromes possess distinctly different binding sites.

Animals↗
PubMed1983

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.

Animals↗
PubMed1983

Reaction of monosubstituted hydrazines and diazenes with rat-liver cytochrome P450. Formation of ferrous-diazene and ferric sigma-alkyl complexes.

The alkyldiazenes RN = NH (R = CH3 or C2H5) react with reduced microsomal cytochrome P450 leading to complexes exhibiting a Soret peak at 446 nm. Upon oxidation of the [cytochrome P450-Fe(II)(CH3N = NH)] complex with limited amounts of dioxygen, a new complex characterized by a Soret peak at 486 nm is formed. The latter complex was also formed upon slow reaction of methyldiazene with microsomal cytochrome P450-Fe(III) or in situ oxidation of methylhydrazine by limited amounts of O2 or ferricyanide. This complex is rapidly destroyed by O2 or ferricyanide in excess and more slowly by excess dithionite in the presence of CO. Reactions of ethyldiazene or benzyldiazene with cytochrome P450-Fe(III) afforded similar complexes characterized by Soret peaks around 480 nm. These results, when compared to those recently described on reactions of monosubstituted hydrazines RNHNH2 and diazenes RN = NH with hemoglobin and iron-porphyrins, are consistent with a [cytochrome P450-Fe(II)(RN = NH)] structure for the 446-nm-absorbing complexes and a sigma-alkyl cytochrome P450-Fe(III)-R structure for the complexes characterized by a Soret peak around 480 nm. They also suggest a sigma-cytochrome P450-Fe(III)-Ph structure for the complex derived from phenylhydrazine oxidation, recently described in the literature. Finally, they provide the first evidence that cytochrome P450-Fe(III)-R complexes are formed upon microsomal oxidation of alkyl or phenylhydrazines.

Animals↗
PubMed1983

A comparison of the protective effects of N-acetyl-cysteine and S-carboxymethylcysteine against paracetamol-induced hepatotoxicity.

The protective effect of the sulphur-containing amino acids N-acetyl-cysteine and S-carboxymethylcysteine against paracetamol-induced hepatotoxicity was evaluated in the hamster by biochemical and histological methods. Of the animals receiving paracetamol alone 25% died within 24 h following administration. All surviving animals showed acute hepatocellular injury and marked loss of cytochrome P-450 and hepatic mixed-function oxidase activities. Simultaneous administration of N-acetylcysteine decreased the mortality rate, partly prevented the paracetamol-induced liver damage and partly restored enzyme activities. Simultaneous administration of S-carboxymethylcysteine with paracetamol afforded no protection. Kidneys from all animals were histologically normal. Human liver microsomes and liver microsomes from 3-methylcholanthrene-pretreated hamsters metabolished paracetamol to intermediate(s) that bind covalently to microsomal proteins. The rate of covalent binding was inhibited markedly by N-acetylcysteine and to a lesser extent by S-carboxylmethylcysteine.

Acetaminophen↗
PubMed1982

Studies on the substrate-binding sites of liver microsomal cytochrome P-448.

The interaction of substrates of the microsomal mixed-function oxidases with cytochromes P-450 and P-448 was investigated by using liver microsomes from rats pretreated with phenobarbital or 3-methylcholanthrene, and with purified forms of the cytochromes isolated from rabbit liver. The two forms of the cytochrome have different substrate specificities; cytochrome P-450 has one type 1 substrate-binding site that can accommodate a large variety of substrates, but in contrast cytochrome P-448 may possess two type 1 substrate-binding sites, one of which is different to that of cytochrome P-450 in that it shows a specificity for substrates such as safrole and 9-hydroxy-ellipticine. These findings explain why the two forms of the cytochrome have different substrate specificities and play contrasting roles in the activation and deactivation of xenobiotics.

Animals↗
PubMed1982

Selective inhibition of the safrole-induced mixed-function oxidase activities by 9-hydroxyellipticine.

Intraperitoneal administration of 9-hydroxyellipticine, a specific cytochrome P-448 inhibitor, inhibited 3-methylcholanthrene-induced cytochrome P-448 activity (ethoxyresorufin O-deethylase, biphenyl 2-hydroxylase) and formation of the safrole carbene ligand complex with this cytochrome, but did not inhibit phenobarbital-induced cytochrome P-450 activity (ethyl-morphine N-demethylase) or formation of the safrole carbene ligand complex with this cytochrome. Biphenyl displaced the 9-hydroxyellipticine ligand from cytochrome P-448 leading to increased free cytochrome, but with no corresponding increase in mixed-function oxidase activity when biphenyl was used as substrate. It is concluded that following dissociation of the ligand complex, 9-hydroxyellipticine, which also exhibits type I binding, competes with biphenyl for the substrate binding site. Administration of 9-hydroxyellipticine to safrole-pretreated rats inhibited the cytochrome P-448-catalysed activity, but had no effect on the cytochrome P-450-catalysed activity. These results indicate that safrole induces a mixture of cytochromes P-450 and P-448 rather than a single novel haemo-protein. The type I substrate biphenyl displaced both the safrole carbene and the 9-hydroxyellipticine ligands from cytochrome P-448 resulting in increased free cytochrome. Displacement of the safrole carbene ligand was accompanied by increased mixed-function oxidase activity but, in contrast, displacement of the 9-hydroxyellipticine ligand resulted in no increase in mixed-function oxidase activity.

Alkaloids↗
PubMed1982

Hepatotoxicity of trichloroethylene-carbon tetrachloride mixtures in rats. A possible consequence of the potentiation by trichloroethylene of carbon tetrachloride-induced lipid peroxidation and liver lesions.

Liver histology was normal 24 h after the administration of trichloroethylene (1 ml . kg-1) in rats. It was normal, or showed necrosis of a few hepatocytes, after the administration of carbon tetrachloride (64 microliters . kg-1). In rats receiving both solvents, there was extensive centrilobular necrosis. In vitro, trichloroethylene did not initiate lipid peroxidation but potentiated that initiated by carbon tetrachloride; a similar potentiating effect was observed for a wide range of trichloroethylene concentrations (0.19-12 mM). In vivo, a wide range of trichloroethylene doses (0.064-1 ml . kg-1) similarly potentiated the hepatotoxicity of carbon tetrachloride. Administration of trichloroethylene (1 ml . kg-1), 5 h earlier, increased carbon tetrachloride-induced lipid peroxidation in vitro, and increased the hepatotoxicity of a subsequent dose of carbon tetrachloride (64 microliters . kg-1). Previous administration of carbon tetrachloride failed to modify lipid peroxidation and to increase the hepatotoxicity of trichloroethylene. We conclude that trichloroethylene potentiates the hepatotoxicity of carbon tetrachloride, possibly by increasing carbon tetrachloride-induced lipid peroxidation.

Animals↗
PubMed1980

Ligand binding of safrole to cytochrome P-450.

Safrole, a hepatocarcinogen, is converted by the microsomal mono-oxygenase system to a reactive intermediate which interacts with cytochrome P-450 to form a ligand complex. The formation of this complex is accompanied by loss of mono-oxygenase activity. The present study describes the interaction of the safrole reactive intermediate with microsomes from phenobarbital, 3-methylcholanthrene and safrole pretreated animals.

Animals↗
PubMed1980

Inhibition of cytochrome P-448 mixed function oxidase activity following administration of 9-hydroxyellipticine to rats.

The in vitro inhibitor of mixed-function oxidation, 9-hydroxyellipticine, non-competitively inhibited the binding of the type II substrate, aniline, to cytochrome P-448 of hepatic microsomal preparations from rats pretreated with 3-methylcholanthrene. In contrast, 9-hydroxyellipticine did not inhibit the binding of aniline to cytochrome P-450 of hepatic microsomal preparations from rats pretreated with phenobarbitone, nor did it inhibit the binding of the type I substrate, hexobarbitone to either cytochrome P-450 or cytochrome P-448. Following the pretreatment of rats intraperitoneally with 9-hydroxyellipticine and phenobarbitone, the cytochrome P-448-specific enzyme activity, ethoxyresorufin O-deethylase, was 50% inhibited in vitro but cytochrome P-450, cytochrome P-450 reductase, and other mixed function oxidase activities were unaffected. With rats pretreated with 9-hydroxyellipticine and 3-methylcholanthrene, inhibition of ethoxyresorufin O-deethylase was 90%, and cytochrome P-450/P-448, cytochrome P-450 reductase, biphenyl 2- and 4-hydroxylase were inhibited by 30, 15, 50 and 40% respectively. It is concluded that 9-hydroxyellipticine administered in vivo markedly inhibits mixed-function oxidations which are specific to cytochrome P-448, but has no effect on cytochrome P-450-catalysed microsomal oxidation.

Alkaloids↗