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Biomedical subjects

P Beaune

Publications and source records attributed to P Beaune.

At least 145 records · Page 8Linked to original sources
PubMed1982

Infantile phytanic acid storage disease, a possible variant of Refsum's disease: three cases, including ultrastructural studies of the liver.

Three cases of phytanic acid storage disease with symptoms during the first months of life are reported. Hepatomegaly, facial dysmorphia, growth and/or mental retardation and osteopenia were observed in addition to retinitis pigmentosa and neurosensory deafness. The presence of phytanic acid in serum (160-320 mumol/1 (50-100 micrograms/ml)) was accompanied by hypocholesterolaemia. Electron microscopy showed that a storage material had accumulated in mesenchymal and parenchymal liver cells. Lamellar structures were seen in hepatocytes and other storing cells. These inclusions resembled the structures found in plant chloroplasts containing phytol. Some of the clinical and biological data obtained were consistent with Refsum's disease. However, other characteristics such as mental retardation, hepatomegaly, osteopenia, hypocholesterolaemia and hypoalphalipoproteinaemia, as well as the ultrastructural findings in the liver, suggested that our patients' illness was either a phytanic acid storage disease different from the classical form of Refsum's disease, or a more severe early symptomatic form of Refsum's disease. Early diagnosis by phytanic acid assay and electron microscopic liver examination calls for prescription of a low phytanate diet in the hope of improving the child's condition.

Child↗
PubMed1982

Drug-metabolizing enzymes in human foetal liver: partial resolution of multiple cytochromes P 450.

Cytochrome P 450 concentration, related monooxygenase activities (towards aniline, p-nitroanisole, benzphetamine, ethoxycoumarin, benzo(a)pyrene, testosterone, and dehydroepiandrosterone), epoxide hydrolase, and glutathione S-transferase activities were measured in the liver of human foetuses aged from 15 to 38 weeks and compared to adult activities. Different ontogenic patterns seem to exist between monooxygenase activities: if the overall cytochrome P 450 concentration, aniline hydroxylase, benzphetamine demethylase, epoxide hydrolase, and glutathione S-transferase activities reach about the half of adult values as early as 15-25 weeks of gestational age, the metabolism of benzo(a)pyrene, ethoxycoumarin, and testosterone in position 6 beta is very low in these foetuses, whereas the 16 alpha hydroxylation of dehydroandrosterone is higher than in adult human liver. Foetal and adult cytochromes P 450 were resolved by DEAE cellulose chromatography into three different fractions: in reconstitution experiments, the major fraction (A) was active toward aniline, whereas benzphetamine and ethoxycoumarin were mainly metabolized by the two other fractions (Ba and Bb). Results show that multiple cytochromes 450 are present in foetal liver and are able to catalyze, with a lower molecular activity, the same reactions as in adult human liver.

Aryl Hydrocarbon Hydroxylases↗
PubMed1981

Cytochrome P-450 monooxygenase activities in human and rat liver microsomes.

Microsomes were prepared from human livers obtained from renal donors of various ages and both sexes. Their drug-metabolizing capacity was measured and compared to that of rat liver microsomes. The following parameters were investigated: cytochrome P-450, cytochrome B5, NADPH-cytochrome c reductase, epoxide hydrolase, aryl hydrocarbon hydroxylase, benzphetamine N-demethylase, p-nitroanisole-O-demethylase, ethoxycoumarin-O-deethylase, steroid-16 alpha-hydroxylase. In addition, the metabolism of benzo(a)pyrene, progesterone, pregnenolone, testosterone, dehydroepiandrosterone and estradiol was studied in detail in vitro. The inhibitory effect of metyrapone and alpha-naphthoflavone on 7-ethoxycoumarin-O-deethylase was measured. The microsomal proteins of both species were separated by polyacrylamide gel electrophoresis in the presence of dodecyl sulfate. The following conclusions were drawn from the results obtained. Human liver microsomes can be stored under optimal conditions for the measurement of a large variety of enzymic activities. Human liver microsomes are able to metabolize the various xenobiotics used as substrates with a rate similar to that of female rat liver microsomes. No sex-linked difference in enzymic activity was observed in human microsomes. Significant differences in benzo(a)pyrene and steroid metabolism were registered when human and rat liver microsomes were compared. The monooxygenase activities, the sensitivity to in vitro alpha-naphthoflavone and metyrapone, the results of steroid metabolism, and slab gel electrophoresis are strong indications for multiplicity of human liver cytochrome P-450.

Animals↗
PubMed1981

Ellipticines and human liver microsomes: spectral interaction with cytochrome P-450 and hydroxylation. Inhibition of aryl hydrocarbon metabolism and mutagenicity.

Some pharmacological properties of ellipticine (E) and its derivatives linked to their interaction with cytochrome P-450 have been investigated with human liver microsomes. 9-Hydroxyellipticine (9-OHE) interacts with human liver cytochrome P-450 exhibiting a type II spectrum (lambda max: 428 nm, Ks = 1.1 microM). After incubation with human liver microsomes the E was converted to 9-OHE; 7-hydroxyellipticine was not produced. The cytotoxic effect of this biotransformation has been evaluated on leukemic L1210 cells, in vitro, and found to be equal to those elicited by liver microsomes of control or phenobarbital (PB) pretreated rats. Moreover, 9-OHE and 9-fluoroellipticine (9-FE) strongly inhibit the benzo[alpha]pyrene hydroxylase (AHH) activity of human liver microsomes (I50 = 2.6 microM and 1.6 microM, respectively) as well as the mutagenesis induced by the polycyclic aromatic hydrocarbon 2-acetylaminofluorene (AAF); 1 microgram/plate of each of these compounds is able to inhibit by more than 50% the mutagenicity of 5 microgram/plate AAF.

2-Acetylaminofluorene↗
PubMed1981

Comparison of the effects of phenobarbital and its hydroxylated metabolites on drug-metabolizing enzymes during ontogenesis.

Twenty-two-day-old fetal and five-day-old newborn rats were pretreated with phenobarbital and its hydroxylated metabolites. Drug-metabolizing enzymes (cytochrome P450, epoxide hydrolase, UDP-glucuronosyltransferase, and glutathione-S-transferase) and microsomal ribonuclease were not modified in fetuses treated with 80 or 400 mg . kg-1 of p-hydroxyphenobarbital, in spite of its accumulation in fetal liver. At fetal age, phenobarbital was a poor inducer of drug-metabolizing enzymes. In five-day-old newborns, p-hydroxyphenobarbital provoked a proliferation of endoplasmic reticulum without enzyme induction, whereas phenobarbital induced some drug-metabolizing enzymes. Thus, the effects of p-hydroxyphenobarbital and phenobarbital are retained in five-day-old rats, but undetectable in the fetuses.

Animals↗
PubMed1980

The use of formic acid in carrier gas. Rapid method for identification and determination of phytanic acid by gas chromatography-mass spectrometry-chemical ionization.

A rapid gas chromatographic method to determine phytanic acid in plasma from Refsum's disease is described. After a brief alkaline hydrolysis of lipids, the biological sample is directly injected into a glass pre-column; an acid carrier gas (formic acid in nitrogen) is used to displace the long-chain fatty acids from their sodium salts and from their binding to proteins. Formic acid introduced through the column may also be used as a reagent gas for chemical ionization in combined gas chromatography--mass spectrometry; fatty acids (C14 to C18:2 and phytanic acid) are easily identified by their M + 1 (base peak) and M - 17 peaks. The described procedure is also suitable for studying normal fatty acids from plasma lipids.

Eicosanoic Acids↗
PubMed1980

[Effects of erythrocytes on electrometric pH measurements (author's transl)].

Erythrocyte interference in electrometric readings has been demonstrated and quantified in pH measurements. The presence of erythrocytes introduces a negative component into the final result of the electrometric reading, proportional to the hematocrit. There is indirect evidence that this does not correspond to a true proton concentration change, but to the presence of the erythrocytes per se. The authors suggest the use of a correcting factor (0.01 pH unit per tens of hematocrit units) to obtain the real pH from a pH value measured on whole blood: however the use of this correcting factor should be restricted to the type of equipment described.

Adult↗
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↗
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↗
PubMed1977

[Origin and fixation of pyrophosphates in the parietal bones of young rats].

Calvaria from 6 to 13-day-old rats mineralize and bind pyrophosphates which are transferred from nucleotides, as shown by : 1 -- the increase of pyrophosphates in young rat calvaria incubated with nucleoside triphosphate, especially ATP ; 2 -- the more important increase of pyrophosphate content when ATP is renewed in the incubation medium ; and 3 -- binding of [32P] pyrophosphate [beta 32P] ATP. The effect of preheating of calvaria on 32P binding from [beta32P]ATP led us to assume that two systems might be involved in pyrophosphate fixation : a heat-labile, non-specific, phosphatase system, and a heat-stable pyrophosphotransferase system. cAMP increases the pyrophosphate content of calvaria incubated with ATP : that effect may result from either an inhibition of the phosphatase system, or an activation of the pyrophosphotransferase system.

Adenosine Triphosphate↗
PubMedDate not supplied

Both cytochromes P450 2E1 and 1A1 are involved in the metabolism of chlorzoxazone.

Chlorzoxazone, a centrally acting muscle relaxant, was previously shown to be hydroxylated on carbon 6 specifically by cytochrome P450 2E1. Accordingly, this drug has been proposed as a potential noninvasive in-vivo probe for screening the hepatic P450 2E1 activity. This study was carried out to test the specificity of such a substrate when first experiments conducted by using human hepatocyte cultures showed that the chlorzoxazone 6-hydroxylation activity increased after 3-methylcholanthrene treatment of cells. Indeed, the ability of both rat and human hepatocytes to metabolize chlorzoxazone significantly increased after treatments by 3-methylcholanthrene alone or plus ethanol, suggesting the involvement of P450 1A enzymes in this oxidative reaction. Identical results were obtained by in-vivo treatment of rats with four inducers of P450 1A enzymes, namely, beta-naphthoflavone, isosafrole, Arochlor 1254, and 3-methylcholanthrene. Furthermore, the chlorzoxazone 6-hydroxylation activity was inhibited by both alpha-naphthoflavone and dimethyl sulfoxide, both known to inhibit P450 1A and P450 2E1 activities, respectively. Finally, the use of yeasts genetically engineered for expression of human P450 1A1, 1A2, 2C9, and 3A4 demonstrated that P450 1A1 was significantly involved in this catalytic activity. In conclusion, these results taken together suggest that chlorzoxazone should be used with precaution as in-vivo tool for evaluating P450 2E1. However, the relative Km of P450 1A1 and 2E1 for chlorzoxazone and, on the other hand, the relative levels of these two enzymes in the human liver suggest that P450 2E1 would generally be the major form metabolizing chlorzoxazone in-vivo.

Adult↗