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S De Flora

Publications and source records attributed to S De Flora.

At least 73 records · Page 4Linked to original sources
PubMed1994

Inhibition of the 'spontaneous' mutagenicity in Salmonella typhimurium TA102 and TA104.

Thirty-four compounds belonging to various chemical classes were assayed for the ability to modulate the 'spontaneous' mutagenicity in strain TA104 of S. typhimurium, and 17 of them were also assayed in TA102. All test agents, many of which were already known or suspected to act as inhibitors of induced mutagenicity, had been previously monitored in our laboratory for antimutagenicity towards either 4-nitroquinoline 1-oxide in TA100 and/or cigarette smoke in TA98 with S9 mix. A considerable proportion of test compounds decreased the number of spontaneous revertants in TA104 (44.1%) and/or TA102 (41.2%) to a significant extent, with dose-related and reproducible effects. In almost all cases the antimutagenic effect was genuine and not related to bacterial killing or growth inhibition. The results obtained suggest that the DNA repair background plays a prominent role in the genesis of spontaneous mutations in these strains, containing the hisG428 mutation which is typically reverted by oxidative mutagens. Due to its theoretical and practical implications, the finding that several chemopreventive agents can attenuate the rate of spontaneous reversion deserves attention.

Antimutagenic Agents↗
PubMed1994

Chemoprevention of carcinogen-DNA adducts and chronic degenerative diseases.

Molecular dosimetry techniques were exploited in order to assess the efficacy of experimental chemoprevention assays and to evaluate the involvement of DNA alterations, not only in cancer but also in other chronic degenerative diseases. In agreement with other protective effects previously observed in the same animal models, the thiol N-acetylcysteine (NAC) totally prevented or significantly reduced the formation of carcinogen-DNA adducts in three experimental systems in rats. Thus, as assessed by 32P postlabeling, supplement of the diet with NAC decreased both deoxyguanosine-C8-aminofluorene adducts (butanol enrichment) and deoxyguanosine-N2-acetylaminofluorene adducts (nuclease P1 enrichment) formed in rat liver following dietary administration of 2-acetylaminofluorene for 3 weeks. DNA adducts were detected by synchronous fluorescence spectrophotometry in rat liver, lung, heart, and testis following a daily i.t. instillation of benzo(a)pyrene for 3 consecutive days. The whole-body exposure of rats to mainstream cigarette smoke for 40 consecutive days resulted in the appearance of DNA adducts in heart, lung, and aorta, whereas no adduct was detected by synchronous fluorescence spectrophotometry in liver, brain, and testis. Multiple DNA adducts in the aorta were also measured by 32P postlabeling. Administration of NAC by gavage inhibited the formation of DNA adducts in all organs of rats treated with benzo(a)pyrene or exposed to cigarette smoke. It is of interest that a single chemopreventive agent can display a broad-spectrum protective ability. The selective localization of DNA adducts in different organs depends on pharmacokinetics, metabolic capacity, DNA repair efficiency, and cell proliferation rate. Whereas inhibition by NAC of DNA adducts in testis can be correlated with its demonstrated ability to prevent dominant lethal mutations, we raise the hypothesis that DNA adducts in lung, heart, and aorta may be pathogenetically associated with lung cancer, cardiomyopathies, and arteriosclerosis, respectively. In order to explore the involvement of molecular and biochemical alterations in human arteriosclerosis, we started an extensive collaborative project and report here preliminary data showing the presence of DNA adducts in aorta smooth muscle cells obtained from arteriosclerotic patients.

2-Acetylaminofluorene↗
PubMed1994

Modulation of diethylnitrosamine carcinogenesis in rat liver and oesophagus.

A series of 16 experiments, using a total of 2,000 BD6 rats, was designed in order to assess the ability of 8 individual agents or their combinations to modulate the liver and oesophageal carcinogenesis induced by multiple doses of diethylnitrosamine (DEN). Of the antioxidants tested, sodium selenite, ascorbic acid, and butylated hydroxytoluene generally exhibited protective effects on both types of tumors. In contrast, retinoic acid behaved as a promoter of DEN hepatocarcinogenesis, but this effect could be eliminated by its combination with either selenite or butylated hydroxytoluene. Caffeine and theophylline, when individually assayed, were devoid of significant protective effects, and the latter methylxanthine stimulated oesophageal tumorigenesis when administered after exposure to the carcinogen. Caffeine tended to decrease the multiplicity of liver tumors and potentiated the inhibitory effect of selenite in the liver. Irrespective of combination with caffeine, treatment with phenobarbital before each DEN injection tended to reduce the multiplicity of both liver and oesophageal tumors. On the other hand, the metabolic inhibitor diethyldithiocarbamate, given after each DEN injection, dramatically enhanced the incidence and multiplicity of oesophageal tumors. Thus, on the whole, modulation of DEN carcinogenesis varied depending on test agents, their combinations, dosages, treatment schedules, and target organ.

Animals↗
PubMed1994

Genotoxicity of mercury compounds. A review.

This article reviews literature data concerning the genotoxicity of 29 mercury-containing agents, including laboratory compounds as well as ingredients of preparations used as fungicides, dyes, disinfectants and drugs. A variety of genetic end-points were investigated in bacteria, yeasts, moulds, plants, insects, cultured cells from fishes, rodents or humans, aquatic organisms, amphibians, mammalia and exposed humans. The overall evaluation is quite complex. Mercury compounds failed to induce point mutations in bacteria but often exerted clastogenic effects in eukaryotes, especially by binding SH groups and acting as spindle inhibitors, thereby causing c-mitosis and consequently aneuploidy and/or polyploidy. Inorganic mercury compounds were also found to induce the generation of reactive oxygen species and glutathione depletion in cultured mammalian cells. Although different mercury compounds tended to produce qualitatively comparable genetic effects, which suggests the involvement of a common toxic entity, methylmercury derivatives and other ionizable organomercury compounds were more active in short-term tests than either non-ionizable mercury compounds (e.g., dimethylmercury) or inorganic mercury salts (e.g., mercuric chloride). The results of cytogenetic monitoring in peripheral blood lymphocytes of individuals exposed to elemental mercury or mercury compounds from accidental, occupational or alimentary sources were either negative or borderline or uncertain as to the actual role played by mercury in some positive findings. Both genotoxic and non-genotoxic mechanisms may contribute to the renal carcinogenicity of mercury, which so far has been convincingly demonstrated only in male rodents treated with methylmercury chloride.

Animals↗
PubMed1994

Experimental databases on inhibition of the bacterial mutagenicity of 4-nitroquinoline 1-oxide and cigarette smoke.

Two antimutagenicity databases were prepared by applying a co-treatment procedure to the Salmonella reversion assay. Ninety compounds belonging to various chemical classes were quantitatively tested for antimutagenicity towards the direct-acting mutagen 4-nitroquinoline 1-oxide (4NQO) in strain TA100 of S. typhimurium and 63 of them were additionally tested for antimutagenicity towards unfractionated mainstream cigarette smoke (CS) in strain TA98, in the presence of S9 mix. Twelve compounds (13.3%) inhibited 4NQO mutagenicity by at least 50%, with a MID50 (dose inhibiting 50% of mutagenicity) varying over a 1226-fold range. Twenty-six compounds (41.3%) inhibited CS mutagenicity, with a MID50 varying over a 520-fold range. Three compounds only, i.e., bilirubin, curcumin and myricetin, were capable of inhibiting the mutagenicities of both 4NQO and CS. However, myricetin and the other flavonoid rutin were at the same time mutagenic by inducing frameshift mutations following metabolic activation. There was a rather rigorous selectivity of antimutagenicity data depending on the chemical class of inhibitors and it was possible to discriminate protective effects within several pairs or series of structurally related compounds. For instance, all eight thiols and aminothiols inhibited 4NQO mutagenicity, which contrasted with the inactivity of the remaining 17 sulfur compounds tested, all of them lacking a free sulfhydryl group. The mutagenicity of CS was consistently inhibited by the majority of phenols (eight out of 10 tested) and by all two isothiocyanates, two dithiocarbamates, three indole derivatives, three tetrapyrrole compounds and three flavonoids tested. Although the results obtained cannot be extrapolated to other mutagens or test systems, they may provide a useful source of information for research in the area of antimutagenesis and for the development of chemopreventive agents.

4-Nitroquinoline-1-oxide↗
PubMed1994

Metabolic activation of a cigarette smoke condensate by woodchuck liver, as related to sex, pregnancy, hepatitis virus infection and primary hepatocellular carcinoma.

The liver S12 fractions from 23 woodchucks were assayed for the ability to activate a cigarette smoke condensate to metabolites inducing frameshift mutations in strain TA98 of S. typhimurium. At equivalent protein concentration, all samples activated this complex mixture to a similar extent, without any significant difference related to sex, hepatitis virus (WHV) infection, or primary hepatocellular carcinoma. Thus, unlike aflatoxin B1, aromatic amines and heterocyclic amines, whose metabolic activation has been shown to be stimulated by WHV infection in the same liver samples used in the present study, genotoxic components present in the particulate of mainstream cigarette smoke do not appear to be more readily biotransformed in vitro by preparations of infected hepatocytes. A significant increase of metabolism was however recorded in a small number of WHV-infected pregnant animals, which deserves attention in the light of the adverse effects of both hepadnavirus infection and cigarette smoking in pregnancy.

Animals↗
PubMed1994

Structural basis of antimutagenicity of chemicals towards 4-nitroquinoline 1-oxide in Salmonella typhimurium.

Eighty-eight organic compounds representing a variety of chemical classes, a proportion of which possess antimutagenic and/or anticarcinogenic properties, were compared for their ability to inhibit the direct-acting mutagenicity of 4-nitroquinoline 1-oxide (4NQO) in strain TA100 of Salmonella typhimurium. Twelve compounds were found to decrease 4NQO-induced mutagenicity by at least 50%, with an antimutagenic potency varying over a 1225-fold range, corresponding to a 4-4900 molar excess of inhibitor over that of 4NQO. The resulting antimutagenicity data base was subjected to structural analysis by the computer automated structure evaluation (CASE) methodology, which identified one structural determinant (biophore) and four biophobes. The biophore contained the sulfhydryl group, present in three thiols and five aminothiols, all of which inhibited 4NQO mutagenicity. Conversely, the corresponding disulphides or thioethers as well as dithiocarbamates, isothiocyanates and other sulfur-containing compounds were devoid of antimutagenicity towards 4NQO. A distinctive dichotomy in the ability to inhibit 4NQO mutagenicity was observed with pairs of structurally and metabolically related compounds, such as the polyamines spermidine (antimutagenic) versus spermine and the tetrapyrroles bilirubin (antimutagenic) versus biliverdine. Curcumin and myricetin were the only inhibitors of 4NQO-induced mutagenicity out of a group of 12 phenols and three bioflavonoids, respectively. One biophobe was an oxidized sulfhydryl moiety, while the other three were derived from benzene or its derivatives. Some of these phenyl compounds are known antioxidants. Thus, nucleophilicity rather than antioxidant properties appears to play a role in antimutagenicity to 4NQO.(ABSTRACT TRUNCATED AT 250 WORDS)

4-Nitroquinoline-1-oxide↗
PubMed1994

Cytosolic activation of aromatic and heterocyclic amines. Inhibition by dicoumarol and enhancement in viral hepatitis B.

The aromatic amines 2-aminofluorene (2AF), 2-acetylaminofluorene, and 2-aminoanthracene, and the heterocyclic amines 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-amino-3,4-dimethylimidazo[4,5-f]quinoline, and 3-amino-1-methyl-SH-pyrido[4,3-b]indole (Trp-P-2) were activated by rat liver cytosolic fractions to form mutagenic metabolites in Salmonella typhimurium strains TA98, TA98NR, and TA98/1,8-DNP6. In the case of the Trp-P-2, the cytosolic activation was even more potent than the microsomal activation, which is classically ascribed to N-hydroxylation and subsequent esterification. The cytosolic activation was a) NADPH-dependent, b) induced by pretreatment of rats with 3-methylcholanthrene and especially Aroclor 1254 but not by phenobarbital, and c) inhibited by dicoumarol. The hypothesis is that, following a preliminary oxidative step in the cytosol (pure cytosolic activation) or in microsomes via prostaglandin H synthase (mixed microsomal-cytosolic activation), an oxidized intermediate of amino compounds may serve as substrate for DT diaphorase activity and bielectronically reduced to the corresponding N-hydroxyamino derivative. Purified DT diaphorase, in the presence of either NADPH or NADH as electron donor, produced mutagenic derivatives from IQ and Trp-P-2. An NADPH-dependent activation of Trp-P-2 also occurred in the liver cytosol of woodchucks (Marmota monax), but was not inhibited by dicoumarol. As previously demonstrated with liver S-12 fractions in both humans and woodchucks, the cytosolic activation of Trp-P-2 was enhanced in animals affected by hepatitis B virus infection. This enhanced metabolism, which persisted even after appearance of primary hepatocellular carcinoma in virus carriers, is likely to be ascribed to mechanisms other than DT diaphorase induction, such as glutathione depletion.

Amines↗
PubMed1993

Genotoxicity of volatile and secondary reactive oxygen species generated by photosensitization.

Reactive oxygen species were generated in the gas phase by photosensitization involving illumination of Rose Bengal. Depending on whether the chromophore is dry or solubilized, this system produces either energy-transfer reactions leading to generation of singlet oxygen specifically, or a combination of energy-transfer and electron-transfer reactions, providing both singlet oxygen and reduced forms of oxygen, such as superoxide anion and hydrogen peroxide. In neither case were the reactive species mutagenic in strain TA104 of Salmonella typhimurium, which had been previously shown to be reverted by oxygen species generated by the hypoxanthine-xanthine oxidase system in aqueous medium. However, mixed oxygen species induced an increased lethality in a variety of DNA repair-deficient Escherichia coli strains. This genotoxic effect, mainly reparable by the uvrA and recA mechanisms, was efficiently prevented by the thiol N-acetyl-L-cysteine. Singlet oxygen itself failed to exert direct genotoxic effects, although secondary reactants produced by its reaction with cell components enhanced lethality in some repair-deficient bacteria. Distance-dependence analyses provided measurements of the lifetimes of the oxygen species generated in the gas phase.

Absorption↗
PubMed1993

N-acetyl-l-cysteine.

The most commonly used chemopreventive agents in the prevention of oral leukoplakia, head and neck cancer, and lung cancer are beta-carotene, vitamin A, and other retinoids. One of the few chemopreventive agents not in this group and presently being used in a clinical trial is N-acetyl-l-cysteine (NAC). NAC, an antioxidant, is used in EUROSCAN, a European Organization of Research and Treatment of Cancer (EORTC) chemoprevention study in curatively treated patients with oral, laryngeal, or lung cancer. The rationale for choosing NAC is based on a variety of experimental data showing its ability to exert protective effects, including extracellular inhibition of mutagenic agents from exogenous and endogenous sources, inhibition of genotoxicity of reactive oxygen species, modulation of metabolism coordinated with blocking of reactive metabolites, protection of DNA and nuclear enzymes, and prevention of the formation of carcinogen-DNA adducts. NAC has also demonstrated an effect on mutagen-induced chromosomal sensitivity assays, and on anticarcinogenicity in experimental animal models. In addition, preliminary data from EUROSCAN show good compliance in treated patients and a low frequency of side effects.

Acetylcysteine↗
PubMed1993

Multiple genotoxicity biomarkers in fish exposed in situ to polluted river water.

Specimens of rainbow trout (Oncorhynchus mykiss) were either kept in an aquarium under laboratory conditions or caged in the River Po (Northern Italy), upstream or downstream the confluence with the River Lambro, a small yet heavily polluted tributary. Genotoxicity biomarkers, evaluating the internal dose or early biological effects, were monitored after 7, 15 and 30 days of in situ exposure. With the exception of a slight increase of aminopyrine-N-demethylase and uridine-5'-diphospho-glucuronosyl-transferase, no significant effect was produced in fish kept upstream the River Lambro, as compared to control fish kept in the aquarium. In contrast, the responsibility of this tributary in carrying sublethal doses of both genotoxic agents and enzyme inducers into the main river was proved by the significant occurrence of early biological alterations in fish caged downstream. In fact, (a) bile extracts contained frameshift mutagens requiring metabolic activation, with a prevalence of liposoluble components after a short exposure, followed by a time-related increase of conjugated components, in minor part with glucuronic acid; (b) the monooxygenases aminopyrine-N-demethylase, uridine-5'-diphospho-glucuronosyl-transferase and, with sharp differences, arylhydrocarbon hydroxylase and 7-ethoxyresorufin-O-deethylase were enhanced in liver microsomal fractions; (c) the liver cytosolic fractions had an enhanced ability to convert 3-amino-1-methyl-5H-pyrido(4,3)indole into mutagenic metabolites in S. typhimurium; (d) cytogenetic damage was demonstrated by an increased frequency of micronuclei in peripheral blood erythrocytes.

Animals↗
PubMed1993

Post-mortem stability of benzo[a]pyrene diolepoxide--DNA adducts in rat organs.

In order to evaluate the stability of benzo[a]pyrene diolepoxide--DNA adducts two separate studies were carried out in rats, either treated i.p. with benzo[a]pyrene (100 mg/kg body wt) or sham-exposed. The measurement of DNA adducts in 155 samples of liver, lung or heart, each of them tested in duplicate, was performed by synchronous fluorescence spectrophotometry. In the first study fragments of rat liver or lung were stored for varying times at varying temperatures. No decrease of adduct levels occurred at 4 degrees C for at least 72 h, whereas a significant decrease was recorded in both liver and lung after 48 h at 20 degrees C or 24 h at 37 degrees C. In the second study liver, lungs and heart were collected from rats either immediately after killing or after storage of cadavers for 16 h at 20 degrees C or 16 h at 20 degrees C plus 24 h at 4 degrees C, thereby mimicking typical storage conditions of human cadavers before autopsy. Under these conditions no significant variation of fluorescent adducts was observed in any organ. In conclusion, at least for this kind of adduct, the use of autopsy samples following proper storage of cadavers seems to be acceptable.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed1993

Induction of micronuclei in cultured human lymphocytes exposed to quartz halogen lamps and its prevention by glass covers.

The light emitted by an uncovered tungsten halogen lamp (12 V, 50 W), equipped with a dichroic mirror, induced time-related and distance-related increases in the frequency of micronucleated lymphocytes following in vitro exposure. Peripheral blood lymphocytes from three healthy donors showed the same degree of sensitivity. This clastogenic effect could be ascribed to the emission of far-UV wavelengths (UVB and UVC) and was prevented by interposing a common glass cover. These results support the findings of our genotoxicity studies in repair-deficient bacteria and carcinogenicity studies in hairless mice, thereby suggesting possible health hazards associated with illumination with halogen quartz bulbs, to which an enormous number of individuals are nowadays exposed. These hazards can be simply avoided by using glass covers.

Adult↗
PubMed1993

Pulmonary alveolar macrophages in molecular epidemiology and chemoprevention of cancer.

In addition to possessing an extraordinary sweeping activity, pulmonary alveolar macrophages (PAM) are equipped with the biochemical mechanisms involved in the metabolism of carcinogens, which were found to be inducible in humans by cigarette smoke. Moreover, several defense processes were stimulated in rat PAM after in vivo administration of the anticarcinogen N-acetylcysteine (NAC). Benzo[a]pyrene diol epoxide (BPDE)-DNA adducts, as revealed by synchronous fluorescence spectrophotometry, were selectively detected in PAM of smokers and persisted up to 6 months. The amount of adducts was significantly correlated with the number of currently smoked cigarettes but not with the cigarettes smoked in a lifetime (pack-years). Nevertheless, deviations from the regression line pointed out the role of interindividual variability factors in adduct formation. Probably due to the low mitotic rate of PAM in the respiratory lumen, the frequency of micronuclei was not enhanced in smokers. However, parallel assays in rats showed that micronuclei can be enhanced after massive intratracheal administration of benzo[a]pyrene or whole-body exposure to high amounts of mainstream cigarette smoke, which also induced BPDE-DNA adducts in lung cells and other organs, including the heart. All these adverse effects were markedly inhibited by the oral administration of NAC, which provides the premise and rationale for a future study on the protective effects of oral NAC in heavy smokers.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed1992

Protection by N-acetylcysteine of the histopathological and cytogenetical damage produced by exposure of rats to cigarette smoke.

Adult male Sprague-Dawley rats were exposed whole-body to mainstream cigarette smoke (CS) once daily for 40 consecutive days. Such a treatment resulted in a significant decrease of body weight growth and in intense histopathological changes of terminal airways, including a severe inflammation of bronchial and bronchiolar mucosae, with multiple hyperplastic and metaplastic lesions and foci of micropapillomatous growth as well as emphysema, with extensive disruption of alveolar walls. All histopathological changes were efficiently prevented by the daily administration of the thiol N-acetyl-L-cysteine (NAC) by gavage. Cytological and cytogenetical changes were monitored in bronchoalveolar lavage (BAL) fluid and bone marrow cells of groups of rats killed after 1, 3, 8, 28, or 40 days of treatment. From the first day of exposure, CS significantly enhanced the proportion of polymorphonucleates among BAL cells and the frequency of micronucleated (MN) bone marrow polychromatic erythrocytes. After 8 days, a reduction was observed in the polychromatic/normochromatic erythrocytes ratio and an increase in the frequency of MN pulmonary alveolar macrophages (PAM) was also recorded, followed, after 28 days, by an increase of binucleated PAM. All these alterations immediately reached a plateau and persisted unchanged until the end of the experiment. NAC administration exhibited a significant and considerable protective effect towards the CS-induced alterations of BAL cellularity, the increase of MN PAM and bone marrow cytotoxicity.

Acetylcysteine↗