Biomedical subjects
Publications and source records attributed to R Royer.
Nitro naphtofurans are powerful mutagenic agents. Subcutaneous injections of 7-methoxy 2-nitro naphtho [2,1-b] furan (R 7000) in C3H mice induce subcutaneous fibrosarcomas at the site of injection and squamous cell carcinomas of the stomach.
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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.
Among the nitro-naphthofurans, 7-methoxy-2-nitro-naphtho[2,1-b]furan (R 7000) has been proved to be a very potent mutagen. The purpose of this study was to demonstrate the carcinogenicity of a R 7000 to male Wistar rats initially 6 weeks old. R 7000 was dissolved in olive oil at a concentration of 1 mg/ml for injection. A S.C. injection of 0.5 ml containing 0.5 mg of R 7000 was given once a week in the neck of each animal tested. Ten control animals were not injected and 10 animals received a 0.5 ml injection of olive oil every week to serve as control. The remaining 70 animals were divided into five groups. Four groups of 10 animals received a total of either 2.5 mg, 5 mg, 7.5 mg or 10 mg of R 7000; the fifth group of 30 animals received 12.5 mg of R 7000. In animals which did not receive R 7000, no malignant tumor was observed. In those to whom R 7000 was administered tumors began to appear at the site of the injection after the third month. At the sixth month of the experiment, most of the animals injected had a tumor at the injection site. The number of tumor-bearing animals and the time between the first injection and the tumor appearance were closely related to the dose of R 7000 injected. These tumors were high grade fibrosarcomas, one animal developed a salivary fibrosarcoma. No other tumors or metastases were found in the autopsied animals. The high carcinogenicity of R 7000 in vivo is analogous to that of methylcholanthrene. The exact mechanism of action of 2-nitro-naphthofurans as carcinogens remains to be explained.
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The disposition of 7-methoxy-2-nitronaphtho[2,1-b]furan (MNNF), labelled with 14C in the furan ring (label 1) and in the methoxy group (label 2) has been studied in rats and mice. After i.p. administration to rat (5 mg/kg), both labelled species were absorbed by the lymphatics; and after oral administration, through the intestinal lumen. Excretion of the furan ring (label 1) is mainly urinary (44% dose in 24 h); label 2 was mostly expired as 14CO2 (48% dose in 24 h), indicating considerable demethylation. No target organ was found for MNNF, except liver and kidney. For both labelled species given orally, radioactivity was bound to the intestinal wall. Preliminary metabolic studies, using t.l.c. and h.p.l.c., have shown the presence of an urinary metabolite, namely, the glucuronide of 7-hydroxy-2-nitronaphtho[2,1-b]furan (15-20% of the urinary radioactivity). The remaining radioactivity comprises basic compounds, that bind to a cationic resin, which might be formed by enzymic reduction of the nitro group.
Nine furothiocoumarins corresponding to psoralen, 8-methylpsoralen, 3-carbethoxy-8-methylpsoralen, 8-methoxypsoralen, pseudopsoralen, angelicin, isopseudopsoralen, allopsoralen and pseudoisopsoralen were synthesized by treating furocoumarins with phosphorus pentasulfide. Photobiological studies on haploid yeast cells (Saccharomyces cerevisiae) revealed that the furothiocoumarins exert some photoactivity on cell survival and the induction of mitochondrial damage. In most cases, the furothiocoumarins were less active than their furocoumarinic counterparts and exhibited a preference for a monofunctional type of action. A certain photochemotherapeutic activity can be suggested.
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We have analyzed the relationship between the biological activities and chemical structure of five naphthofurans. The compounds studied included 2-nitro-7-methoxynaphtho[2,1-b]-furan (R 7000) (Compound A), 2-nitro-8-methoxynaphtho[2,1-b]-furan (Compound B), 2-nitronaphtho[2,1-b]furan (Compound C), 2-nitro-7-bromonaphtho[2,1-b]furan (Compound D), and 7-methoxynaphtho[2,1-b]furan (Compound E), the nonnitrated analogue of Compound A. The genotoxic activities of the compounds were studied in V79 cells using the micronucleus, sister chromatid exchange, and hypoxanthine-guanine phosphoribosyltransferase locus mutation tests. This allowed us to classify their mutagenic properties in the following order: A congruent to B much greater than C greater than D greater than E. However, in the in vivo short-term skin tests, the order in activities of the first three compounds is reversed, and the five compounds can be classified in decreasing rank of potency: C greater than B greater than A greater than or equal to E congruent to D. The two compounds tested for in vitro transformation, Compounds A and B, demonstrated a positive effect in both the C3H10T1/2 and the Syrian hamster embryo cell systems. The biological activities of Compounds A, B, C, and D appeared to be strongly linked to the presence of a NO2 group in position 2. These activities were enhanced or decreased by a methoxy group in position 7 or 8. Almost all activities were suppressed if the methoxy group in position 7 was replaced by a bromine (Compound D). The positive results obtained in the cell transformation assays and in the short-term skin tests indicate that Compounds A, B, and C are probably carcinogenic. Therefore, further in vivo studies should be accomplished before using the 2-nitronaphthofuran derivatives in human and animal treatments.
Two 2-nitronaphthofuran derivatives exhibited a dose-dependent lethal effect on Rous sarcoma virus-tranformed chicken embryo fibroblasts. When they were added at time of infection, they prevented cell transformation, but not virus replication, in a dose-dependent manner. Since the two derivatives inhibited mainly the DNA sythesis, we assume that they altered some early DNA-dependent cell event required for cell transformation and not for the integration of provirus.
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2-nitro 7-methoxy naphtho [2,1-b] furan (R 7000) and 2-nitro 8-methoxy naphtho [2,1-b] furan, which are highly mutagenic on the bacterium Salmonella typhimurium have little activity on the yeast Saccharomyces cerevisiae. Nevertheless, irradiation at 365 nm elicits a weak but significant increase of their mutagenic activity on this yeast.
The genetic toxicity of benzofurans and naphthofurans was further examined. (i) Seven new 2-nitronaphthofurans tested give a positive response on strains TA1537, TA1538, TA98, TA100, but not on strain TA1535. This response depends at least partially on the bacterial nitroreductase activities and is decreased in presence of activating mixture from rat liver. (ii) A correlation is observed between the mutagenic potency assayed in the Mutatest and the phage-inducing potency assayed in the Inductest. The relevance of these results and of complementary tests on uvr + Salmonella strains and the Spermatest are briefly discussed in perspective of the possible genetic toxicity of the compounds on mammals.
A group of 2-nitrobenzofurans possessing antibacterial and antiparasitic properties have now been shown to be potential radiosensitizers from investigations in simple aqueous solution by pulse radiolysis and from survival studies in yeast. The radical anions of several 2-nitrobenzofurans were formed by the rapid reaction of the parent molecules with hydrated electrons or with various pyrimidine electron adducts. Studies of equilibria between these radical anions, the parent nitrobenzofurans and the corresponding species derived from quinones with known one-electron reduction potentials, showed that the one-electron reduction potentials of all the furans under investigation lie between -285 and -309 mV. They are thus more electron affinic than the nitroimidazoles (misonidazole and metronidazole) currently under clinical evaluation. 5-Hydroxy- and 7-hydroxy-2-nitrobenzofuran were demonstrated to form weak complexes with DNA (binding constant 80 M-1) and strong complexes with HSA (binding constant 10(5)M-1). In the yeast Saccharomyces cerevisiae the nitrobenzofurans exert radiosensitizing effects on survival either similar to or higher than misonidazole.
A series of benzofurans and naphthofurans was examined through the Salmonella/microsome assay. (i) With one possible exception, only 2-nitro derivatives give a mutagenic response. However, it appears that the mutagenic potency depends notably on the nature and the position of the other substituents in the molecule. (ii) The mutagenic response occurs in strains TA1537, TA1538, TA98 and TA100 but not in strain TA1535. Reversion of the missense mutation of TA1535 is thus induced only in presence of the plasmid pKM101. (iii) This mutagenic response is at least partially dependent on the bacterial nitroreductase activities and is usually lower in presence of activating mixture from rat liver. (iv) One of the compounds tested, 2-nitro-7-methoxynaphtho[2,1-b]furan (R7000), may be the most potent mutagen examined so far in the Salmonella/microsome assay. It yields about 200 000 revertants/nanomole on strain TA100 in the standard plate test. The relation between structure, mutagenic potency and other biological activities of the compounds are briefly discussed.