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Mutagenesis of cytoplasmic factors in eukaryotic organism
124
triazenes in group C (X = 4-carboxy; 2-carboxy) and in group D (X = 4-methyl; 4-methoxy; 4-acetamino), no mutagenic effect was observed in S. typhimurium G-46 in the presence or absence of liver microsomal fraction. The survival rate was <80% and <20%, respectively. Incubation of triazenes in class A with liver supernatants of phenobarbitonepretreated mice enhanced the mutagenic effect by 2 to 10 times compared with liver supematant from untreated mice. Since strain G-46 is reverted to his’by base-pair substitutions, triazenes of group A and B act as monofunctional alkylating agents following metabolic activation. The high toxicity of 4-methoxy and 4-acetamino derivatives (group D) was strongly decreased by a 9,000 g mouse liver supernatant, but only when NADP’ and glucoseS-phosphate were present. With 3,3-dimethyl-l-phenyltriazene as substrate, liver fractions from BD-Vl or BD-V rats caused a lower enzyme mediated mutagenicity in S. typhimurium G-46 than mouse liver, while the 9,000 g supernatant from brain, a major target organ for the carcinogenic action of triazenes was unable, in both species, to generate metabolites mutagenic for S. typhimurium G-46. The reaction mechanisms, whereby biologically active triazene metabolites are generated, will be discussed.
41 P.P. Puglisi and F. Restivo, Parma (Italy) Mutagenesis
Institute
of cytoplasmic
of Genetics,
factors in eukaryotic
University
of Parma,
organism
DNA in eukaryotic organism is present not only in chromosomes but also in sub-cellular organelles which an increasing amount of evidences indicate as being concerned with the expression of nuclear determinations. Furthermore, many chemicals which are devoid of any detectable mutagenic effect on nuclear determinations appears strongly mutagenic on extra-chromosomal DNA. These fact poses a series of problems that will be discussed: - the relationship between extrachromosomal information and nuclear genes expression - the selective pressure of extrachromosomal events on nuclear information - the evaluation of extrachromosomal mutation - the nature of extrachromosomal mutagens.
42 C. Donnini,
Institute
R. Franchini, G. Pacchetti and C. Rossi, of Genetics, University of Parma, Parma (Italy)
Genetic effects (Largactil) The
drug
of 2-chloro-10
2-chloro-10
(3dimethylaminopropyl)-phenothiazine
(3-dimethylamino
propyl)-phenothiazine
has been
125
studied from the following point of view: -- in vitro interaction with DNA -- spontaneous forward mutation in S. cerevisiae: nuclear genes -- spontaneous forward mutation in S. cerevisiae: extrachromosomal genes -- somatic recombination in S. cerevisiae -- meiosis and spore survival in S. cerevisiae -- human chromosome in vivo -- human chromosome in vitro The results will be discussed, with particular attention to the methodological problems.
43 B. Krajin~aniS, A. Lazarov, Z. ~uni5 and Radoji~id, Institute "B. Kidric", Radiobiological Laboratory, and Military Medical Academy, Belgrade (Yugoslavia) The chromosomal changes in the patients suffering from malignant diseases during radio and chemotherapy The aim of this investigation was the determination of the relation between the clinical course and frequency of chromosomal abnormalities in patients suffering from leukemia and lymphosarcoma after the therapy with X-rays and the cytostatic " M e t h o t r e x a t e " . Patients were treated with therapeutic doses of Methotrexate and X-rays. The cytogenetic investigations of peripheral blood and bone marrow cells suggest an increased frequency of numerical and structural chromosomal abnormalities, such as: peripheral blood cells with 47 and 44 chromosomes polyloid cells, dicentric chromosomes, extra long chromosomes, chromatid breakage and endoreduplication.
44 K.P. Grosse, G. Schwanitz and W.D. Rummel, Universit~itskinderklinik, Erlangen (Federal Republic of Germany) Secondary c h r o m o s o m e aberrations in parents, a causative factor of congenital heart defect? Chromosome analyses were perfomed on 11 newborns with congenital heart defect, and also on their parents. The rate of secondary c h r o m o s o m e aberrations in this group was compared with the data of 11 healthy newborns and their parents. The following average aberration rates were found (percentage of aberrant mitoses): healthy newborns 7.6%, newborns with congenital heart defect 6.5%; parents of healthy newborns: mothers 6.6%, fathers 6.6%; parents of newborns with congenital heart defect: mothers 8.8%, fathers 7.7%.
triazenes in group C (X = 4-carboxy; 2-carboxy) and in group D (X = 4-methyl; 4-methoxy; 4-acetamino), no mutagenic effect was observed in S. typhimurium G-46 in the presence or absence of liver microsomal fraction. The survival rate was <80% and <20%, respectively. Incubation of triazenes in class A with liver supernatants of phenobarbitonepretreated mice enhanced the mutagenic effect by 2 to 10 times compared with liver supematant from untreated mice. Since strain G-46 is reverted to his’by base-pair substitutions, triazenes of group A and B act as monofunctional alkylating agents following metabolic activation. The high toxicity of 4-methoxy and 4-acetamino derivatives (group D) was strongly decreased by a 9,000 g mouse liver supernatant, but only when NADP’ and glucoseS-phosphate were present. With 3,3-dimethyl-l-phenyltriazene as substrate, liver fractions from BD-Vl or BD-V rats caused a lower enzyme mediated mutagenicity in S. typhimurium G-46 than mouse liver, while the 9,000 g supernatant from brain, a major target organ for the carcinogenic action of triazenes was unable, in both species, to generate metabolites mutagenic for S. typhimurium G-46. The reaction mechanisms, whereby biologically active triazene metabolites are generated, will be discussed.
41 P.P. Puglisi and F. Restivo, Parma (Italy) Mutagenesis
Institute
of cytoplasmic
of Genetics,
factors in eukaryotic
University
of Parma,
organism
DNA in eukaryotic organism is present not only in chromosomes but also in sub-cellular organelles which an increasing amount of evidences indicate as being concerned with the expression of nuclear determinations. Furthermore, many chemicals which are devoid of any detectable mutagenic effect on nuclear determinations appears strongly mutagenic on extra-chromosomal DNA. These fact poses a series of problems that will be discussed: - the relationship between extrachromosomal information and nuclear genes expression - the selective pressure of extrachromosomal events on nuclear information - the evaluation of extrachromosomal mutation - the nature of extrachromosomal mutagens.
42 C. Donnini,
Institute
R. Franchini, G. Pacchetti and C. Rossi, of Genetics, University of Parma, Parma (Italy)
Genetic effects (Largactil) The
drug
of 2-chloro-10
2-chloro-10
(3dimethylaminopropyl)-phenothiazine
(3-dimethylamino
propyl)-phenothiazine
has been
125
studied from the following point of view: -- in vitro interaction with DNA -- spontaneous forward mutation in S. cerevisiae: nuclear genes -- spontaneous forward mutation in S. cerevisiae: extrachromosomal genes -- somatic recombination in S. cerevisiae -- meiosis and spore survival in S. cerevisiae -- human chromosome in vivo -- human chromosome in vitro The results will be discussed, with particular attention to the methodological problems.
43 B. Krajin~aniS, A. Lazarov, Z. ~uni5 and Radoji~id, Institute "B. Kidric", Radiobiological Laboratory, and Military Medical Academy, Belgrade (Yugoslavia) The chromosomal changes in the patients suffering from malignant diseases during radio and chemotherapy The aim of this investigation was the determination of the relation between the clinical course and frequency of chromosomal abnormalities in patients suffering from leukemia and lymphosarcoma after the therapy with X-rays and the cytostatic " M e t h o t r e x a t e " . Patients were treated with therapeutic doses of Methotrexate and X-rays. The cytogenetic investigations of peripheral blood and bone marrow cells suggest an increased frequency of numerical and structural chromosomal abnormalities, such as: peripheral blood cells with 47 and 44 chromosomes polyloid cells, dicentric chromosomes, extra long chromosomes, chromatid breakage and endoreduplication.
44 K.P. Grosse, G. Schwanitz and W.D. Rummel, Universit~itskinderklinik, Erlangen (Federal Republic of Germany) Secondary c h r o m o s o m e aberrations in parents, a causative factor of congenital heart defect? Chromosome analyses were perfomed on 11 newborns with congenital heart defect, and also on their parents. The rate of secondary c h r o m o s o m e aberrations in this group was compared with the data of 11 healthy newborns and their parents. The following average aberration rates were found (percentage of aberrant mitoses): healthy newborns 7.6%, newborns with congenital heart defect 6.5%; parents of healthy newborns: mothers 6.6%, fathers 6.6%; parents of newborns with congenital heart defect: mothers 8.8%, fathers 7.7%.