Genotoxic activity of three carcinogens in peripheral blood erythrocytes of the newt Pleurodeles waltl.
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2-Naphthylamine↗
Biomedical subjects
D Marzin
Publications and source records attributed to D Marzin.
Differences in genotoxic activity of alpha-Ni3S2 on human lymphocytes from nickel-hypersensitized and nickel-unsensitized donors.
The genotoxic activity of alpha-Ni3S2 was assessed on human lymphocytes from nickel-hypersensitized (SSL) and nickel-unsensitized (USL) subjects. Three genotoxicity tests were performed: the sister chromatid exchange (SCE) test, the metaphase analysis test and the micronucleus test. (i) The SCE test (3-100 micrograms/ml) showed a weak but statistically significant increase in the number of SCE in both lymphocyte types with respect to controls, USL presenting a slightly higher SCE incidence but only at one concentration. (ii) The metaphase analysis test demonstrated a high dose-dependent clastogenic activity of alpha-Ni3S2 in both lymphocyte types. The frequency of chromosomal anomalies was significantly higher in USL than in SSL for all concentrations applied. (iii) The micronucleus test confirmed the dose-dependent clastogenic activity of alpha-Ni3S2 and the differences already observed between USL and SSL, i.e. the number of cells with micronuclei was statistically higher in USL. Finally, the incorporation study with alpha-63Ni3S2 showed a higher uptake of its solubilized fraction by USL. This allows an explanation of the different genotoxic action of nickel on the two cell types. In this study we demonstrated that hypersensitivity has an influence on the incorporation of alpha-Ni3S2 and subsequently on the different induction of chromosomal aberrations in human lymphocytes.
Adult↗
Trenbolone: application of the Ames test. Recent data.
The mutagenicity of trenbolone, a synthetic androgen, was studied in a number of genotoxicity tests using in vitro and in vivo systems for gene mutations, chromosomal mutations and primary DNA damage demonstration. Only 2 tests were found to be positive or dubious: the in vitro micronucleus test in SHE cells (however, this test was negative in 2 other cell lines: C3H and CHO cells) and the Ames test for 1 of the 5 studies which found a positive result in TA 100 strain without metabolic activation. Repetition of this study with pure trenbolone showed no genotoxic activity; trenbolone was therefore considered to be devoid of genotoxic activity.
Anabolic Agents↗
Genotoxic activity of nickel subsulphide alpha-Ni3S2.
Four mutagenicity tests of alpha-Ni3S2 were performed: the Ames test on five Salmonella typhimurium strains, HPRT test on V79 cells, in vitro chromosomal aberrations on human lymphocytes and the in vivo micronucleus test in mice. The in vitro tests were carried out without metabolic activation. (i) The Ames test (5-1500 micrograms/plate) demonstrated no mutagenic activity, thus confirming previous observations by other authors. (ii) The HPRT test was carried out under standard conditions (3 h exposure) with alpha-Ni3S2 concentrations from 30 to 1000 micrograms/ml. No significant difference was observed with the control cells. Ultrastructural examination revealed alpha-Ni3S2 binding to the cell membrane. Very few particles were found in the cytoplasm but not in the nucleus. (iii) In vitro metaphase analysis in human lymphocytes were performed after exposure to total alpha-Ni3S2 suspension and to the soluble fraction in culture medium with or without fetal calf serum (FCS) (3-100 micrograms/ml, 24 h exposure). Nickel concentrations in the soluble fraction were determined by electrothermal atomic absorption spectrometry. A clastogenic effect of alpha-Ni3S2 became evident under all experimental conditions with a significant additional increase of chromosomal aberrations in 20% FCS complemented medium. No difference was observed between total suspension and soluble fraction. (iv) The micronucleus test confirmed the clastogenic effect of alpha-Ni3S2 in vivo after administration of 250 mg/kg (i.p.). This test revealed a clear increase of micronuclei frequency in polychromatic erythrocytes 24, 48 and 72 h after the treatment. In addition, we observed a statistically significant decrease in the number (%) of polychromatic erythrocytes after 24 and 48 h exposure. The soluble, i.e. cell-entering, fraction seems to play a great part in the clastogenic effect, as has also been shown with other test methods by other authors.
Animals↗
Determination of the LDL receptor binding capacity of human lymphocytes by immunocytofluorimetric assay.
The determination of the LDL receptor binding capacity of human blood lymphocytes was assessed by indirect immunocytofluorimetric assay. To produce the maximal synthesis of the LDL receptor, the cholesterol efflux was enhanced by incubation of lymphocytes with HDL3 subfractions. The binding capacity of the LDL receptor was measured by incubation at 4 degrees C either with LDL and rabbit anti-LDL immunoglobulins or with peptide receptor antibody (ARP-Ig) raised against the NH2-terminal sequence of the LDL receptor. Thereafter complexes were incubated with fluorescein-labelled anti-rabbit immunoglobulin (FITC-Ig). Fluorescence flow cytometry was used to quantify the number of fluorescent lymphocytes and results were expressed as the percentage of lymphocytes with a fluorescent intensity above the threshold. Using preimmune rabbit immunoglobulin and then FITC-Ig, only 5-10% of cells were fluorescent. Neither LDL nor ARP-Ig could bind to homozygous familial hypercholesterolemia (FH) lymphocytes. Normal lymphocytes preincubated with HDL3 could bind LDL or ARP-Ig, the number of fluorescent cells being 59 and 39.2% respectively. Subjects with confirmed or suspected heterozygous FH demonstrated cell fluorescence at about half the normal level.
Female↗
SOS Chromotest study concerning some appreciation criteria of humic substances' genotoxic potency.
The genotoxicity of 5 compounds: 2 fulvic acids, a trade humic acid, a synthetic humic material (SHM), and 2,5-dihydroxybenzoic acid, was assessed after chlorination, by means of the SOS Chromotest for tester strain E. coli PQ 37 without metabolic activation. Chlorination was carried out for humic material concentration of 0.5 mg total organic carbon per liter, and chlorine concentrations in the range of 0.1-2.0 chlorine equivalents per mole of carbon. Among all the considered criteria that can account for potent toxicity: chemical degradation determined by the UV absorption decrease, chlorine consumption, average molecular weight, only the polymerization index (O.D. 665 nm/O.D. 465 nm) can be related to the genotoxicity of humic samples. This latter criterion appears a possible predictor of genotoxic potency, revealed subsequent to the aqueous chlorination of humic materials. Looking at the various genotoxic activities of the tested compounds, SHM can be considered a better model of natural humic materials than the trade humic acid.
Alkaline Phosphatase↗
[Utilization of genotoxicity tests for biological surveillance of personnel exposure].
Monitoring of those staff exposed to products or atmospheres containing carcinogenic substances may be carried out using genetic toxicology tests. These tests may highlight primary DNA modifications, genetic or chromosomal mutations, detect mutagens at the urinary level or assess a global effect, expressed by a genotoxic effect. All these tests must be used taking into account exposure kinetics, the substance in question and exposure conditions.
Humans↗
Effects of fenofibrate, gemfibrozil and nicotinic acid on plasma lipoprotein levels in normal and hyperlipidemic mice. A proposed model for drug screening.
These studies examine the effects of a hypercholesterolemic diet (with butter and cholesterol added), or a hypertriglyceridemic diet (30% sucrose (w/v) in drinking water), on murine plasma lipids and lipoproteins prepared either by sequential ultracentrifugation or gel exclusion chromatography. The hypercholesterolemic diet increased plasma cholesterol (186%), particularly that associated with very low (VLDL) and low (LDL) density lipoproteins. In addition, the cholesterol/triglyceride ratio in the VLDL fraction rose significantly from 0.10 to 4.0. The hypertriglyceridemic diet raised markedly plasma triglyceride levels (46%) by expanding the circulating VLDL pool (+39%). These dietary modifications were used to provide a model for the examination of 3 classical hypolipidemic drugs (fenofibrate, gemfibrozil and nicotinic acid). In animals receiving the standard diet, fenofibrate, gemfibrozil and nicotinic acid decreased the triglyceride (TG) level (-28%, -31%, and -38%) by lowering VLDL-TG (-37%, -42%, and -49%), fenofibrate and gemfibrozil increased HDL-cholesterol by 18% and 31%, respectively. In animals receiving the hypercholesterolemic diet fenofibrate lowered the total plasma cholesterol level by 40%, at the same time increasing HDL-cholesterol by 23%. In animals fed sucrose, on the other hand, fenofibrate (100 mg/kg per day) and nicotinic acid (900 and 600 mg/kg per day) reduced plasma triglyceride levels (-20%, -40% and -33%), and nicotinic acid (900 mg/kg per day) decreased VLDL-TG by 58%. These results are in good agreement with clinical data from studies in man and suggest that this animal model may provide a useful and rapid screening system for testing new lipid lowering drugs.
Animals↗
Effects of fenofibrate on lipoprotein metabolism and fatty acid distribution in Zucker rats.
The short term effects of fenofibrate (150 mg/kg per day), administered by gavage, on lipoprotein and fatty acid distribution have been investigated in an hypertriglyceridemic model, the Zucker rat. Lean rats were compared to control obese and treated obese rats, and control obese animals to treated obese littermates. Classically, plasma cholesterol and triacylglycerol increased by 1.8- and 7.9-fold, respectively, in control obese versus lean rats. Treatment of the Zucker obese rats with fenofibrate reduced their plasma cholesterol by 10% and raised triacylglycerol by 47% (P less than 0.001) in comparison to untreated control obese rats. These effects were accompanied by a change in the composition of all plasma lipoproteins. The cholesterol/triacylglycerol ratio in VLDL rose by 32% while that in LDL and HDL fell by 43 and 47%, respectively. Drug therapy altered the fatty acid profile in both plasma and liver; the percentage of polyunsaturated fatty acids fell while monounsaturated fatty acids increased. The increased proportion of monounsaturated fatty acids in plasma suggests that the fatty acid composition of circulating lipoproteins is modified, particularly in VLDL. This, in association with the altered lipid distribution in VLDL may reflect an abnormal metabolism of this lipoprotein. In view of these abnormalities, we conclude that this rat is not an appropriate model for the short-term study of clofibrate analogues.
Animals↗
Aspects of cholesterol metabolism in normal and hypercholesterolemic Syrian hamsters. Influence of fenofibrate.
This study reports the short-term effects of fenofibrate in golden Syrian hamsters receiving a standard or cholesterol enriched (0.5%) diet. In chow fed control animals, the plasma cholesterol (132 mg/dl) was transported essentially by LDL (27%) and HDL (56%). Conversely, the bulk of triglycerides (114 mg/dl) circulated in VLDL (54%). One week of hypercholesterolemic diet increased plasma cholesterol (+80%) and it is reflected in a 3.3-fold increase in VLDL, 2.8-fold in IDL, 1.6-fold in LDL and 1.5-fold in HDL, accompanied by a rise in cholesterol hepatic level by a factor of 4.5. 15 days of treatment with fenofibrate (300 mg/kg/d) produced a decrease in free plasma cholesterol (-21%) without modification in total cholesterol level in chow fed animals. In liver, cholesterol was reduced by 27% and triglycerides were raised by 58%. In animals receiving the hypercholesterolemic diet, fenofibrate increased hepatic and plasmatic triglyceride levels (55 and 54%, respectively), although it slightly reduced plasma cholesterol levels and more markedly the hepatic cholesterol content (-55%). In chow fed animals, cholesterol biosynthesis was decreased by fenofibrate treatment by 40%. The effects of fenofibrate on triglyceride levels are in contrast to experiences in other animal species, including man, and indicate a hypersecretion of chylomicrons and/or a hypersecretion of VLDL, although the explanations are not yet obvious. The results concerning cholesterol metabolism indicate similarities between man and hamster.
Animals↗
Study of the genotoxic potential of 48 inorganic derivatives with the SOS chromotest.
The genotoxic potential of 48 inorganic derivatives was studied using the bacterial colorimetric assay: the SOS Chromotest. Some of these compounds are known as carcinogens (As, CR(VI), Cd, Ni) or suspected carcinogens for human beings (Hg, Pb), others are known as non-carcinogens. Among these 48 derivatives, only the two Cr(VI) compounds and the Sn(II) compounds gave positive results.
Animals↗
Study of mutagenic activity of troxerutin, a flavonoid derivative.
Troxerutin, a flavonoid derivative, used in vascular diseases was studied in 4 mutagenicity tests: the Ames test, the point mutation test (V79/HPRT), the in vitro metaphase analysis in human lymphocytes and the micronucleus test in mice. The aglycone trihydroxyethylquercetin (THEQ) and quercetin were studied too. Troxerutin was not mutagenic, whereas quercetin was positive in the Ames test, V79 cells and in vitro metaphase analysis. THEQ was negative in the Ames test. The substitution of quercetin with hydroxyethyl groups in 7,3' and 4' positions abolished mutagenic activity of quercetin.
Animals↗
[Theory and practice of genetic toxicology tests. Tests on eukaryotes].
The search for a mutation prone activity on bacteria must be completed by tests on eucaryotes, in vitro as well as in vivo. Tests on eucaryotes enable to study agents inducing gene mutations [on yeats, cultures of mammal cells (V 79, L 5278 Y), lethal recessive mutation linked to the sex chromosome, on drosophils...], chromosomal mutations (metaphases analysis in vitro and in vivo, micronucleus, lethal dominance), the involvement of repair mechanisms of DNA (non-programmed DNA synthesis, exchange of sister chromatides...). One must well differentiate the tests usable routinely for a screening from the tests currently validated and routine tests. It is only at the completion of a set of tests on bacteria and eucaryotes cells that the potential mutation risk of a product for human health, may be ascertained.
Animals↗
[Proposal for a strategy for research on mutagenic effects].
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Cell Line↗
Mutagenicity of eight anthracycline derivatives in five strains of Salmonella typhimurium.
The mutagenicity of eight anthracycline derivatives, doxorubicin (adriamycin, ADM), daunorubicin (DNR), rubidazone (zorubicin), detorubicin (DTR), 4'-epi-adriamycin (4' epi-ADM), AD 32, N-leucyl daunorubicin (N-leu DNR) and aclacinomycin A, has been tested on Salmonella typhimurium TA 100, Ta 98, TA 1535, TA 1537 and TA 1538. All but aclacinomycin A were mutagenic. Adriamycin and daunorubicin were mutagenic in all five strains, but only at very high doses (40-100 micrograms/plate) in TA 1535 and 1537. TA 98 was the most sensitive strain. In general S9 mix (liver homogenate) increased the mutagenicity of the low doses of both compounds. Zorubicin, 4'-epi-adriamycin and detorubicin were mutagenic for TA 98 and TA 100 and slightly mutagenic in TA 1538. They were also activated by S9 mix. N-leu DNR and AD 32 were slightly but significantly mutagenic for TA 98 and TA 1538 and were also activated by S9 mix. Aclacinomycin A lacked mutagenic activity in the five strains even at cytotoxic doses, both in the presence and absence of S9 mix. The results with AD 32 N-leu DNR and aclacinomycin A strengthen the hypothesis according to which amino moiety of the anthracycline glycosides is essential for mutagenesis.
Aclarubicin↗
The reproductive and developmental toxicity profile of beta-cyclodextrin in rodents.
A 3-generation study with two mating phases per generation and a teratology phase was performed in the rat to assess the reproductive and developmental toxicity of beta-cyclodextrin (beta-CD) in the diet. Transient neonatal growth retardation occurred with 5% beta-CD: a similar, but equivocal, effect was also observed with 2.5%. No permanent defects or other indications of developmental toxicity were found. There was no significant maternal toxicity. The dietary level of 1.25% was found to be a NOAEL for developmental toxicity. Further investigations showed the growth retardation to be specific to dietary administration during lactation: it was not produced by parenteral (i.p.) administration and was not influenced by treatment of the dams or litters during gestation. Slight maternal nutritional deficiency, caused by physico-chemical interactions of beta-CD with nutrients in the gut is proposed as the mechanism of action. No difference in milk composition was found.
Animals↗
Quantitative determination of dibekacin using radioimmunoassay, substrate-labelled fluorescent immunoassay and rate nephelometric inhibition immunoassay for tobramycin.
Radioimmunoassay, rate nephelometric inhibition immunoassay and substrate-labelled fluorescent immunoassay were employed for the quantitative determination of dibekacin in serum. The cross-reactivity of the antibody provided with each assay allowed the use of tobramycin assay procedures for measuring dibekacin concentrations. With radioimmunoassay and nephelometric immunoassay, a dibekacin calibration curve was required, whereas fluorescent immunoassay was directly suitable for dibekacin assay, with cross-reactivity of nearly 100%. This allows the purchase of one assay kit for testing two antibiotics and thus reduces the cost to medical laboratories.
Cross Reactions↗