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Biomedical subjects

G Bellucci

Publications and source records attributed to G Bellucci.

At least 37 records · Page 2Linked to original sources
PubMed1991

Effect of a terpenoid, (-)-6-hydroxy-4-(1-hydroxy-1-methylethyl)-1-cyclohexene-1-ethanol, on drug-metabolizing enzymes and glutathione content in rat liver and lung.

1. Chronic treatment of Sprague-Dawley rats with the new terpenoid mucoregulating drug (I) did not modify activities of the drug-metabolizing enzymes (phase I and phase II) of liver and lung. 2. Acute treatment of rats with I did not affect the GSH content of liver and lung, but administration of the corresponding alpha, beta-unsaturated ketone (II) produced considerable GSH depletion in both tissues, the original GSH levels being restored after a few hours. 3. The results are discussed in comparison with those previously obtained with the structurally related drug trans-sobrerol (III).

Animals↗
PubMed1989

The low reactivity of 5H-dibenzo[a, d]cycloheptene 10,11-oxide in microsomal epoxide hydrolase catalysed hydration.

1. The rate of hydration of 5H-dibenzo[a, d]cycloheptene 10,11-oxide catalysed by rabbit liver microsomal epoxide hydrolase has been compared with that of the acyclic analogue cis-stilbene oxide. The latter was shown to be a much better substrate for the enzyme than the former epoxide. 2. The kinetic parameters for the hydration of 5H-dibenzo[a,d]cycloheptene 10,11-oxide and cis-stilbene oxide have been determined using a rabbit liver microsomal preparation at 37 degrees C and pH 7.4. The much slower hydration of the former is due to a much lower Vs and not to a higher Km relative to the latter epoxide. 3. 5H-Dibenzo[a,d]cycloheptene 10,11-oxide inhibited the hydration of cis-stilbene oxide by rabbit liver microsomal epoxide hydrolase.

Animals↗
PubMed1989

Effects of trans-sobrerol on drug metabolizing enzymes in the rat.

1. Metabolism of 14C-trans-sobrerol (I) by Sprague-Dawley rat liver microsomes did not result in covalent binding to proteins, lipid peroxidation or cytochrome P-450 destruction. 2. Subacute and chronic treatment of Sprague-Dawley rats with (I) resulted only in an increase in liver cytosolic GSH-S-transferase. 3. Acute treatment of rats with trans-sobrerol or its metabolite, 8-hydroxycarvotanacetone (II) produced considerable GSH depletion, faster in the case of II, in both liver and lung; the original GSH levels were restored within 24 h. No significant increase in lipid peroxidation was found even when GSH was at its lowest level. 4. UDP-glucuronyltransferase and GSH-S-transferase conjugation occurred with trans-sobrerol and some of its metabolites although at low rates.

Animals↗
PubMed1987

The metabolism of carbamazepine in humans: steric course of the enzymatic hydrolysis of the 10,11-epoxide.

Carbamazepine 10,11-oxide (1a,10b-dihydro-6H-dibenzo[b,f]oxireno[d]azepine-6-carboxamide), a key intermediate in carbamazepine metabolism, was found to be unusually resistant to enzymatic hydrolysis when incubated with microsomal and cytosolic fractions from rabbit, rat, and guinea pig livers. However, its hydrolysis product, trans-10,11-dihydro-10,11-dihydroxy-5H-dibenzo[b,f]azepine-5-carboxamide , was excreted, as previously reported, both in the free and in conjugated forms, as the main metabolite in the urine of humans under carbamazepine treatment. The free diol and that obtained after treatment with beta-glucuronidase/arylsulfatase were both found by Mosher's method to be formed in an enantiomeric excess of 80%, the prevalent enantiomer having the (-)-10S,11S absolute configuration, as determined by applying the CD exciton coupling method to its bis[p-(dimethylamino)benzoyl] ester. This finding confirms the pronounced enantioselectivity of the microsomal epoxide hydrolase toward meso and racemic substrates, but is in contrast with the prevalent formation of (R,R)-diols in most other known cases of enzymatic hydrolysis of epoxides. Preparatively useful syntheses of the racemic trans-10,11-dihydro-10,11-diol and of 9-(hydroxymethyl)-10-carbamoylacridan, another carbamazepine metabolite, are reported for the first time.

Adult↗
PubMed1986

A simple conductimetric method as an alternative to the colorimetric p-nitrobenzylpyridine test for the measurement of the reactivity of potentially mutagenic alkylating compounds.

A simple method for the measurement of the kinetics of reaction of potentially mutagenic alkyl halides with amines, based on the direct conductimetric monitoring of the quaternary ammonium salt produced in these reactions, is proposed and applied to the alkylation of p-nitrobenzylpyridine (NBP) and triethylamine (TEA) in different solvents. With respect to the classical colorimetric NBP-test, this method has the advantage that the rates can be measured continuously over the entire course of the reactions and the kinetic order and constants can be easily obtained. It is also shown that the previously proposed, NBP modified test', using simultaneously NBP and TEA, gives actually the sum of the rate constants for the reactions of the alkylating reagent with the two amines.

Alkylation↗
PubMed1984

Structure activity relationship of epoxides: different mutagenicity of the two diastereoisomeric 3-bromo-1,2-epoxycyclohexanes.

The mutagenic activities in V79 Chinese hamster cells and the alkylating abilities towards nicotinamide of the two diastereisomeric cis and trans-3-bromo-1,2-epoxycyclohexanes were measured and compared with those of unsubstituted 1,2-epoxycyclohexane and bromocyclohexane. trans-3-Bromo-1,2-epoxycyclohexane exhibited a mutagenic activity 2.5 times higher than that of its cis diastereoisomer, but very similar to that of the parent unbrominated epoxide, whereas the electrophilic reactivities towards nicotinamide were very similar for the three epoxides tested. Bromocyclohexane showed the highest toxicity, but no alkylating ability. The presence of an epoxide hydrolase activity in the V79 Chinese hamster cells used in the mutagenesis tests has been demonstrated using safrole oxide as the substrate, cis-3-Bromo-1,2-epoxycyclohexane, but not its trans diastereoisomer, is hydrolyzed by the enzyme present in microsomal preparations from the V79 cells. The results indicate that for the cycloaliphatic compounds examined: (1) the introduction of a bromide substituent at the carbon adjacent to the oxirane ring does not cause an increase in mutagenicity, (2) the relative stereochemical configuration at the above carbon does affect the biological activity and (3) the significantly different mutagenicity of the two diastereoisomeric 3-bromo-1,2-epoxycyclohexanes is not attributable to a different electrophilic reactivity, but could be related to some specific interaction with detoxifying enzymes present in the V79 Chinese hamster cells used in the biological experiments.

Alkylation↗
PubMed1984

The reaction of 3,4-epoxy-1-butene with deoxyguanosine and DNA in vitro: synthesis and characterization of the main adducts.

The reaction of guanosine with 3,4-epoxy-1-butene in acetic acid gives two main products of N-7 alkylation. After acidic hydrolysis the two aglycones have been isolated by h.p.l.c. and shown to be the regioisomeric 7-(2-hydroxy-3-buten-1-yl) guanine (I) and 7-(1-hydroxy-3-buten-2-yl) guanine (II), arising through nucleophilic attack by N-7 of the purine at the two oxirane carbons of 3,4-epoxy-1-butene. Spectral characteristics of both compounds are presented, including u.v., 1H-n.m.r. and mass spectra. Deoxyguanosine reacts with 3,4-epoxy-1-butene in 50% methanol-water at 37 degrees C to give the N-7 alkylated deoxynucleosides corresponding to I and II in a 59:41 ratio. The reaction rate depends on the nucleoside concentration, with second order rate constants at 37 degrees C of 1.6 X 10(-2) and 1.1 X 10(-2) h-1 M-1 for the formation of the two deoxynucleoside adduct corresponding to I and II, respectively. The same two compounds I and II in a similar (54:46) ratio have been identified after acidic or thermal hydrolysis of DNA which had been reacted with 3,4-epoxy-1-butene under similar conditions. The half life for the spontaneous depurination of I and II in the adducted DNA under physiological conditions (37 degrees C, pH 7.2) is 50 h.

Apurinic Acid↗
PubMed1983

Metabolism of 1,3-cyclohexadiene by isolated rat liver cells.

The metabolism of 1,3-cyclohexadiene by hepatocytes from phenobarbital induced rat has been investigated. Parenchymal cells were obtained by liver perfusion with a hyaluronidase-collagenase mixture. The addition of the diene to a suspension of hepatocytes gave rise to a type I difference spectrum indicating the formation of an enzyme-substrate complex with cytochrome P-450. The subsequent metabolic pathway of 1,3-cyclohexadiene has been shown to involve, as the first step, the formation of 1,2-epoxy-3-cyclohexene, which is rapidly hydrolyzed to trans-3-cyclohexene-1,2-diol and trans-2-cyclohexene-1,4-diol by a non-enzymatic process. The monoepoxide could not be detected in the incubation medium because of its high reactivity. Therefore, kinetic parameters of the epoxidation reaction were determined by following the rate of production of the diols. When incubated with hepatocytes, trans-3-cyclohexene-1,2-diol, the main product of 1,3-cyclohexadiene metabolism, elicited a reverse type I spectrum, indicating that this compound is not a good substrate for the monooxygenase system.

Animals↗
PubMed1982

The metabolism of 1,3-cyclohexadiene by liver microsomal mono-oxygenase.

1. 1,3-Cyclohexadiene exhibits type I binding spectra with microsomal cytochrome P-450 of either untreated, or phenobarbital- or 3-methylcholanthrene-treated mice. In all cases, two values of Ks can be measured, indicating a different affinity of 1,3-cyclohexadiene towards the cytochrome P-450 species. 2. Mouse-liver microsomal mono-oxygenase metabolizes 1,3-cyclohexadiene to the corresponding mono-epoxide, which is rapidly hydrolysed to trans-3-cyclohexene-1,2-diol and trans-2-cyclohexene-1,4-diol. This hydrolysis was proved to be essentially nonenzymic. 3. A simple gas-chromatographic method was used to quantify the diols and to determine the kinetic constants (Km and Vmax) of 1,3-cyclohexadiene mono-epoxidase. 4. Epoxide formation, as determined by diol production from 1,3-cyclohexadiene metabolism, was NADPH- and O2-dependent and was inhibited by CO and SKF-525A.

Animals↗
PubMed1981

[Antibacterial chemotherapy in resuscitation. Our clinical experience].

Experience with antibiotic management in a resuscitation centre between 1974 and 1978 is described. An account is given of the incidence of bacteria in excreate, urine, blood, etc. cultures, and of the sensitivity of germs most commonly encountered in such centres to single antibiotics. It is shown that Gram-negative bacteria, particularly Pseudomonas aeruginosa, predominate, and the way in which their sensitivity to antibiotics varies in the course of time is examined. Preparation of an "overall antibiogram" based on assessment of the data made it clear that aminoglycosides and cephalosporins are the drugs of choice for Gram-negative forms, and cephalosporins for Gram-positive bacteria. A critical survey of the results leads to the suggestion that four changes should be made in the approach to antibiotic therapy: 1) elimination of the practice of "preventive" therapy in the form of "initial cover"; 2) withdrawals on admission for bacteriological determinations; 3) abstention or administration of a low-toxicity antibiotic (one of the penicillins) in the case of "minor" infection; 4) employment of potent bactericides of the aminoglycoside group or the polymixines only in cases of superinfection with evidence of septicaemia supported by an antibiogram. It is felt that the essential premiss to sound antibiotic management is the removal of other routes where by infection can enter. Drastic supplementary measures must be taken with regard to the architecture of the premises and the sterilisation of material. Staff training is also essential to prevent the spread of infection from hyperseptic patients.

Anti-Bacterial Agents↗
PubMed1980

[Changes in rat liver enzymatic activity induced by CT 1341 (althesin) administration].

Six enzyme activities with different intracellular localization were selected for a study of the metabolic effects caused by CT 1341 (Althesin). Glucose-6-phosphato-phosphatasic, ATP-asic and aryl-4-hydroxylasic (hydroxylasic aniline) activities are in fact localised in the microsomial fraction whereas glucose-6-phosphato-dehydrogenasic, 6-phosphogluconic dehydrogenasic and UDP-glucoso-dehydrogenasic activities are to be found in the soluble fraction. The Althesin doses used varied between 0.75 and 6 mg/kg body weight, but only the latter dose is capable of triggering significant variations. With the exception of glucose-6-phosphato-phosphatase, which falls markedly, and ATPase which behaves discontinuously, the other enzyme activities increase to reach their maximum between the 15th and 30th minute after treatment. The diminution in glucose-6-phosphato-phosphatasic activity is attributable to a drug-induced change in the microsomial membranes. The increase in other activities, on the other hand, is connected with drug metabolisation. On a par with other steroid compounds, CT 1341 to be eliminated, must go through a hydroxylation reaction requiring higher production of NADPH. Its elimination also requires a higher concentration of UDP-glucuronic. The data obtained with separate injection of the active principles making up the drug did not give results in agreement with those obtained with the commercial product and, for the present, no final conclusions can be drawn.

Adenosine Triphosphatases↗