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Biomedical subjects

R Royer

Publications and source records attributed to R Royer.

At least 19 recordsLinked to original sources
PubMed1989

In-vivo carcinogenicity of 2-nitro-oxaphenalenes.

2-Nitro-oxaphenalenes are synthetic chemicals which were synthesized in the authors' laboratory. They are the most efficient mutagenic compounds on mammalian cells in culture. They are chemically related to the nitro-naphthofuran family by the displacement of the heterocycle on the naphthalene ring. Since nitro-naphthofurans have a strong mutagenic activity in bacterial tests without metabolic activation and are active in-vivo carcinogens, the purpose of this study was to demonstrate the carcinogenic activity of two 2-nitro-oxaphenalenes. The two compounds were injected s.c. into Wistar rats initially 6-weeks-old. They were dissolved in dimethylsulfoxide (DMSO) at a concentration of 1 mg/ml. A s.c. injection of 0.5 ml containing 0.5 mg of carcinogen was given once a week in the neck of each animal tested. Five control animals were not injected and five animals received 0.5-ml injection of DMSO every week to serve as a control. The animals developed tumors only at the site of injection. The tumors were classified as high grade fibrosarcomas. This experiment demonstrates that: (i) 2-nitro-oxaphenalenes are very active in-vivo carcinogens in rats; (ii) there is a good correlation between the high mutagenic activity especially in mammalian tests and the strong carcinogenicity of the compounds; and (iii) the presence of a 6-methoxy group increases by two-fold the carcinogenic potential.

Animals↗
PubMed1989

DNA adduct formation by 7-methoxy-2-nitro-naphtho[2,1-b]furan (R7000), an extremely potent mutagen.

The effects on DNA, in bacteria, of 7-methoxy-2-nitro-naphtho[2,1-b]furan (R7000), a very potent genotoxic product from the 2-nitronaphthofuran series, were investigated with two different approaches: (i) measurement of the binding of the radiolabelled mutagen to DNA and (ii) detection by the '32P-postlabelling' method of DNA adducts following treatment with unlabelled mutagens. The covalent binding of R7000 to DNA in Escherichia coli was demonstrated by both methods, and in the latter case it was found to involve the formation of nine different adducts. Formation of adducts by R7000 was shown to require metabolic activation of the compound.

Chromatography, Thin Layer↗
PubMed1989

Macrofilaricidal activity of metabolites of diethylcarbamazine.

The antifilarial compound diethylcarbamazine (N,N-diethyl-4-methyl-2-piperazine, DEC) is known rather for its micro- than macrofilaricidal activity. But in some human filariasis i.e. loaiasis, lymphatic filariasis, the spectrum of DEC activities extends to adult filaria. The potential role of the metabolites of DEC in the action of the parent drug once it had been metabolized in the body of infected animals was investigated. The metabolites were evaluated in a new experimental model on which DEC is active: Molinema dessetae in its natural host, the rodent Proechimys oris. Experimental studies were carried out in vivo and in vitro, on microfilariae, infective larvae and adult filaria. Several other nematodes were also used. The metabolites were DEC itself, N-ethyl-4-methyl-1-piperazine-carboxamide (MEC) and their N-oxides, 4-methyl-piperazine-carboxamide and N,N-diethyl-1-piperazine-carboxamide. In vivo most of the metabolites were found active on microfilariae and both N-oxides active on adults and infective larvae. In vitro, the activity of the metabolites was observed only with high concentrations; the in vitro test could not be used as a screening method for antifilarial chemotherapy with piperazine derivatives. Infective larvae were the most sensitive stage. In the rodent and in man, the antifilarial action of DEC is swift and of short duration. This action is prolonged by the activity of metabolites, especially the N-oxides.

Animals↗
PubMed1988

Evaluation of the genotoxic activity of 2-nitroanthrafurans.

We measured the genotoxic activities in two bacterial tests, the Salmonella/histidine assay (a reverse mutation assay) and the SOS chromotest (an assay for SOS induction in E. coli), of three 2-nitroanthrafurans: 2-nitroanthra[1,2-b]furan (R-7688), the isomeric compound 2-nitroanthra[2,1-b]furan (R-7686) and its 8-methoxylated derivative (R-7707). Their genotoxic activities were compared to that of 7-methoxy-2-nitronaphtho[2,1-b]furan (R-7000) which has been studied in previous works (Arnaise et al., 1986). We found that: (1) for all three 2-nitroanthrafurans, as generally observed for other 2-nitrofuran derivatives, the responses were correlated in the 2 tests and were decreased in the presence of an 'activating mixture' and in nitroreductase-deficient strains; (2) in contrast to what is usually observed with other 2-nitrofuran derivatives for which methoxylation increases genotoxic activity, the genotoxic activity of the methoxylated 2-nitroanthrafuran (R-7707) was comparable and may be even lower than that of the unsubstituted 2-nitroanthrafuran (R-7686); (3) the addition of a third ring that leads from 2-nitronaphthofurans to 2-nitroanthrafurans increased slightly the genotoxic activity of these compounds; (4) compounds with the oxygen heteroatom outside the 'bay region', R-7686 and R-7707, gave higher responses than their isomers with the oxygen heteroatom within the 'bay region', R-7688.

Animals↗
PubMed1988

Oxidative metabolism of 7-methoxy-2-nitro-naphtho[2,1-b]furan (R 7000) by the microsomal system isolated from 3-methylcholanthrene-induced rat liver.

The metabolism of 7-methoxy-2-nitro-naphtho[2,1-b]furan and the subsequent binding to DNA, under aerobic conditions, were investigated using liver microsomes of both untreated rats and rats pre-treated with 3-methylcholanthrene [3-MC]. The metabolites were analyzed by HPLC. The following compounds: 7-hydroxy-2-nitro-naphtho[2,1-b]-furan-6,9-dione; 6,7-dihydro-2-nitro-naphtho[2,1-b]furan; 7-hydroxy-2-nitro-naphtho[2,1-b]furan and 6-hydroxy-7-methoxy-2-nitro-naphtho[2,1-b]furan have been identified by their UV-visible, mass spectra, NMR spectra and by comparison to an authentic reference sample. Qualitative and quantitative metabolic charts involving only ring oxidation have been established.

Animals↗
PubMed1987

Reactivity with DNA of three pyrenofuran analogues of benzo(a)pyrene and benzo(e)pyrene.

Three pyrenofurans, the pyreno[1,2-b]furan (FP1), the pyreno[2,1-b] furan (FP2) and the pyreno[4,5-b]furan (FP3) have been synthesized as analogues of the mutagenic and carcinogenic benzo(a)pyrene (FP1 and FP2) and of its non-carcinogenic isomer benzo(e)pyrene (FP3). For each of the pyrenofurans, the reactivity with DNA has been tested in presence of liver microsomes of rats induced with 3-methylcholanthrene. Fluorescence spectroscopy showed that only FP2 and FP3 which possess a "bay region" react with DNA. In both cases, metabolites bound to DNA have a fluorescence emission comparable to that of the "bay region" dihydrodiols obtained after the "in vitro" metabolism of initial molecules. FP2 is shown to react similarly to benzo(a)pyrene whereas the reactivity of FP3 is different from that of benzo(e)pyrene, in spite of their structural similarities. This is probably due to reasons of three-dimensional space configuration. The peculiar reactivity of FP3 is predicted by calculations of the bond order values.

Animals↗
PubMed1987

Comparison of the carcinogenic effects of two 2-nitro-naphthofurans injected sub-cutaneously in rats.

7-Methoxy-2-nitro-naphtho[2,1-b]furan (R 7000) and its methylated homolog in position 1 (R 7372) are among the most mutagenic agents presently known, as shown by the results obtained both in the Ames test and in the SOS Chromotest. Their carcinogenic effects were tested in rats. We were able to confirm the carcinogenic effects of these nitro-naphthofurans, the presence of a methyl group--while increasing the mutagenic effect of R 7000 10 times--induces a significant decrease of the carcinogenic effects in R 7372. The discrepancy between the mutagenic effects in bacterial assays and the carcinogenic effects of these two 2-nitro-naphthofurans remains to be explained.

Animals↗
PubMed1987

Initiating, promoting and carcinogenic activities of three naphthofurans in a mouse skin long-term study.

The initiating, promoting and carcinogenic activities of three naphthofurans, 2-nitro-7-methoxynaphto[2,1-b]furan (A), 2-nitronaphtho[2,1-b]furan (C) and 7-methoxynaphtho[2,1-b]-furan (E), were determined in a long-term assay using CD1 mice, by means of a two-step skin painting regimen. Compound A was a strong initiator and a weak carcinogen, and compound C was a strong promotor and a moderate carcinogen, whereas compound E did not have any effect. The NO2 group at the 2 position on the molecule was concluded to be responsible for the carcinogenic activity of the former two naphthofurans. The addition of a CH3O group at position 7 enhanced the initiating ability while it diminished the promoting and carcinogenic potentials. These findings indicate that the initiating activity is closely linked to the mutagenic potential previously detected in in vitro and in vivo mammalian cell systems, while the promoting and carcinogenic activities are related to the effects detected in mouse short-term skin tests.

Animals↗
PubMed1987

Mode of action of nitro-heterocyclic compounds on Escherichia coli.

The inhibitory and bactericidal activities of several different nitro-heterocyclic compounds, such as nitrofuran, nitronaphthofuran, nitrobenzofuran, nitroimidazole and nitrothiazole, were assessed in vitro. All these substances except nitroimidazole were active against Escherichia coli, though to different degrees. Under anaerobic test conditions the antibacterial activity increased slightly. Nitroreductase-deficient mutants, however, were highly resistant to all nitro-compounds, indicating that only when the nitro-group is reduced to these agents get into an active antibacterial form. SOS repair-deficient strains were much more susceptible to the nitro-containing substances than repair-proficient counterparts, indicating that damage to bacterial DNA is the essential mechanism of antibacterial activity of all nitro-heterocyclic compounds.

Escherichia coli↗
PubMed1986

Genotoxic activity of two furan analogues of benzo[a]pyrene and their 2-nitro derivatives.

We measured the genotoxic activities in two bacterial tests, the Salmonella/histidine assay (a reverse mutation assay) and the SOS Chromotest (an assay for SOS induction in E. coli), of two pairs of isomeric furan analogues of benzo[a]pyrene: pyreno[1,2-b]furan (R7490) and pyreno[2,1-b]furan (R7692) and their 2-nitro derivatives, 8-nitro-pyreno[1,2-b]furan (R7489) and 8-nitro-pyreno[2,1-b]furan (R7691). We found that: For all 4 compounds, the responses were correlated in the two tests. For the 2-nitro derivatives, R7489 and R7691, the responses were extremely high, reaching SOS-inducing potencies of 5.2 X 10(3) and 10(5)/nmole in the SOS Chromotest and mutagenic potencies of 6.3 X 10(4) and 3.7 X 10(7) revertants/nmole in the Salmonella/histidine assay (strain TA98), respectively; the responses were only slightly decreased in nitroreductase-deficient strains. The responses to the two pyrenofurans were increased in the presence of an "activating mixture" but were still lower than that to benzo[a]pyrene. In contrast to benzo[a]pyrene and pyreno[2,1-b]furan (R7692), pyreno[1,2-b]furan (R7490) also gave a response in the absence of an "activating mixture". (5) Compounds with the oxygen heteroatom within the "bay region" gave lower responses than their isomers with the oxygen heteroatom outside the "bay region".

Animals↗
PubMed1986

Carcinogenic effect of 7-methoxy-2-nitro-naphtho[2,1-b] furan (R 7000) in the forestomach of rats.

7-methoxy-2-nitro-naphtho[2,1-b] furan (R 7000), known as a very potent mutagen and a very active in vivo carcinogen was employed here to develop squamous cell carcinoma in the rat. Seventy male Wistar rats received R 7000 p.o. dissolved in deionized water with 5% ethanol for periods from 1 to 21 months, while 20 served as controls receiving either water or 5% ethanol. All the animals were killed 21 months after the beginning of the experiment. Microscopic lesions were noticed in the forestomach after only 1 month of R 7000 administration. Histologic features varied from slight dysplasia to invasive carcinoma. Their sizes and invasive character increased significantly with the amount of R 7000 administered (P less than 0.05). R 7000 can be considered as a locally acting carcinogen since its carcinogenic effects appear at a place where the compound collects after swallowing. R 7000 is a weak carcinogen at the concentration employed here, when compared to some nitrosamines used in the development of forestomach cancer in rodents. The exact mechanism of the carcinogenic effects remains to be explained.

Animals↗
PubMed1986

Effect of different nitroheterocyclic compounds on aerobic, microaerophilic, and anaerobic bacteria.

The antibacterial activities of different nitroheterocyclic compounds were assessed by an agar dilution method against aerobic, microaerophilic, and anaerobic bacteria. Nitronaphthofurans inhibited the multiplication of aerobic bacteria at low concentrations (MIC for 50% of strains tested [MIC50], 1 mg/liter). Under anaerobic growth conditions the MICs were found to be even lower. The rough, DNA repair-deficient mutants of Salmonella typhimurium were more susceptible, whereas nitroreductase-deficient strains were resistant. Microaerophilic campylobacter isolates could be divided into two groups, one of which was as susceptible as aerobic bacteria (MIC50, 1 mg/liter) and the other of which was more highly susceptible (MIC50, 0.015 mg/liter). All anaerobic bacteria tested were susceptible to nitronaphthofurans (MIC50, 0.125 mg/liter). Nitrothiazole exerted antibacterial activities similar to those of the nitronaphthofurans. Metronidazole, a nitroimidazole derivative, and nitrofurans were definitely less active. Nitrobenzofurans showed relatively high MICs.

Anti-Bacterial Agents↗
PubMed1986

Main excretion metabolites of 7-methoxy-2-nitronaphtho[2,1-b]furan (R 7000) in rats.

Major metabolites, isolated from rat bile and urine after administration of a single dose of 7-methoxy-2-nitronaphtho[2,1-b]furan (R 7000; MNNF) labelled with 14C on the furan ring and on the methoxy group, were identified by comparison of their chromatographic behaviour and mass spectra with synthetic authentic reference compounds. Analysis of metabolites indicated three metabolic pathways for this compound in vivo, namely, demethylation of the methoxy group, hydroxylation of the aromatic ring and cleavage of the furan ring, followed by the reduction of the nitro group to amine.

Administration, Oral↗
PubMed1985

[Evolution of plasma histamine after midazolam in patients at risk of histamine liberation].

Changes in plasma histamine levels 2 min (t1) and 10 min (t2) after the intravenous injection of 0.2 mg X kg-1 midazolam were measured in 10 subjects at risk of releasing histamine (group I) and compared with those of 15 other subjects free from any risk of releasing histamine (group II). There was mean increases in plasma histamine levels of 0.78 ng X ml-1 between t0 and t1 (p less than 0.01), and of 0.41 ng X ml-1 between t0 and t2 (p less than 0.01) in group I; they only rose by 0.18 ng X ml-1 between t0 and t2 (p less than 0.01) in group II. The only statistically significant variation between the two groups was that at t1 (p less than 0.03): plasma histamine levels rose higher at the second minute in those cases at risk. This was a rather small increase, within physiological limits, and without any clinical or haemodynamic manifestation.

Adult↗