Sister-chromatid exchanges in human metabolizing system

Sister-chromatid exchanges in human metabolizing system

215 of mutants that can be biochemically characterized by their altered primary gene products. 96 Quinto, I., and E. De Marinis 1, I1 Istituto di Chi...

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215 of mutants that can be biochemically characterized by their altered primary gene products.

96 Quinto, I., and E. De Marinis 1, I1 Istituto di Chimica Biologica, II Facolt/l di Medicina e Chirurgia di Napoli, and 1 Ente Farmacologico Italiano, S.p.A., Naples (Italy) Effects of propineb and dowtherm A on sperm morphology in mice. Sperm morphology assay in mice has been proposed as an in vivo test for mutagenicity since it was shown to be effective in the detection of several mutagens and carcinogens. By using this test system we performed a toxicological study on different classes of chemicals. Mainly we studied the effects of propineb and dowtherm A in (C57BL/6 × C3H)F 1 male mice according to the method of Wyrobek, A.J., et al. (Proc. Natl. Acad. Sci. (U.S.A.), 72 (1975) 4425). Propineb (zinc propylenebisdithiocarbamate) and dowtherm A (73.5% diphenyl ether and 26.5% biphenyl) are widely used chemicals, the former as a fungicide for tobacco and grape growing, the latter as a heat exchanger in resin and fiber industry. Statistical analyses were performed on the percentage of abnormal sperm measured in treated mice compared to sham-treated controls. No evidence of increase in aberrant sperm was found in mice treated with propineb and dowtherm A. MMS and AAF, used as positive controls, produced a significant increase in sperm abnormalities. This research was partly supported by CNR, Italy, Contract No. 79.01485.90.

97 Raposa, T., and F. Grhf, III. Department of Medicine, Semmelweis University Medical School, 1121. Budapest, E6tv6s u. 12 (Hungary) Sister-chromatid exchanges in human metabolizing system One of the most intriguing problems of the assessment of potential dangers to human of various environmental factors, chemicals, drugs, etc. comes from the extrapolation of the results from non-human systems to man. The two endpoints of chromosomal changes i.e. chromosomal aberrations and SCEs evoked by these agents are largely influenced by species and tissue specificities and characteristics of the metabolic activation system. One approach to overcome these difficulties is to use human metabolizing systems: (1) studying SCEs in somatic cells of human beings exposed to mutagenic agents (chemotherapy, irradiation etc.), (2) studying the effect of plasma withdrawn from patients exposed to mutagenic compounds on the frequencies of SCEs of

216 lymphocytes of non-exposed, clinically healthy persons. The latter system represents a real human metabolizing condition and is recommended to further clarify if a real hazard to man is posed by various suspected mutagenic compounds. If PHA-stimulated lymphocytes of normal donors are cultured in the presence of sera derived from cancer patients under cytostatic therapy the frequency of SCEs is only influenced by the remaining active metabolites of the cytotoxic drugs in the plasma. From the experiments with 27 patients it can be concluded that Ara-C does not cause any increase in SCEs if plasma is taken from the patients 2 h after cessation of the administration of the drug (10 patients) but it increases SCE frequency if it was taken at 10, 30 and 90 min after the end of therapy (6 patients). Alkylating agents such as busulphan and cyclophosphamide caused an increase in SCEs even between 2 and 17 days after the cessation of therapy (8 patients). Hydroxyurea and 5-fluorouracil (2 patients) did not cause any increase in SCEs in this cross-experimental system during therapy similarly to chlorambucil (1 patient) which did so 14 days after the therapy had been terminated. The results lead to two conclusions: (1) When studying SCEs in lymphocytes of patients exposed to cytostatics the effective plasmatic metabolites should be taken into consideration as inducers of SCEs. Differences among subjects in their metabolizing systems could account for divergences of the results between laboratories. (2) The system is a real human metabolizing condition thus making extrapolation of the results to man much more reliable.

98 Raposa, T., L. Sr6ter, Zs. Poll/tk, J. V/lrkonyi and J. Feh+r, III. Department of Medicine, Budapest (Hungary)

SCE in human 'metabolizing system'. The assessment of DNA damage caused by cytostatic therapy and its modification by a dihydroquinoline-type antioxidant The effect of plasma derived from leukemic patients under cytostatic therapy on the frequencies of SCEs in the lymphocytes of normal donors was studied. Patients under Ara-C, cyclophosphamide, busulphan, vincristine as well as combined chemotherapy were studied. In all cases there was a high increase in the frequencies of SCEs in these so called 'cross-experiments', except for those under vincristine therapy. In addition the effect of a new antioxidant, 6,6methylene-bis(2,2,4trimethyl-l,2-dihydroquinoline)4 (Hungarian Pat. No. 162 358, OTH, Budapest, 1975, p. 12) was studied in the same type of cross-experiment. It was shown that this compound was capable of reducing the frequencies of SCEs considerably when cyclophosphamide was given. This compound has been shown to be a radiosensitizer (Pollfik et al., 1979) and these experiments revealed its modifying effect on SCEs. It seems tempting to interpret the results in the light of a mechanism involved in the formation of induced SCEs as well as in the protection against DNA damage.