Hycanthone: A Frameshift Mutagen

Hartman, Philip; Levine, K.; Hartman, Zlata; Berger, Hillard

doi:10.1126/science.172.3987.1058

Cited by 146 publications

(31 citation statements)

References 24 publications

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“…Intercalating mutagens that can form a covalent bond with DNA, such as the quinacrinehalf mustard mutagen ICR 191, are much more active in reverting frameshift mutations in strains without the excision repair system than in strains able to repair damaged DNA (14)(15)(16). By contrast, the absence of this repair system has no effect on the potency of simple intercalating mutagens such as quinacrine or 9-aminoacridine or hycanthone (14,15,21). This difference in mutation frequency between the uvrB+ and uvrB-strains (Table 1) is about 100-fold with 2-nitrosofluorene as the mutagen; large differences are also observed with the other active nitroso compounds, N-hydroxy-2-aminofluorene, and 2-nitrofluorene.…”

Section: Resultsmentioning

confidence: 99%

Carcinogens as Frameshift Mutagens: Metabolites and Derivatives of 2-Acetylaminofluorene and Other Aromatic Amine Carcinogens

Ames

Gurney

Miller

et al. 1972

Proc. Natl. Acad. Sci. U.S.A.

302

121

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Several carcinogenic metabolites of the carcinogen 2-acetyl-aminofluorene, especially 2-nitrosofluorene and N-hydroxy-2-aminofluorene, are potent frameshift mutagens for Salmonella typhimurium. 2-Nitrosonaphthalene, 2-nitrosophenanthrene, 4-nitroso-transstilbene, 4-nitrosobiphenyl, and 4-nitrosoazobenzene, all of which are metabolites or likely metabolites of carcinogenic aromatic amines, are also potent frameshift mutagens. These compounds may be frameshift mutagens of the class that intercalates into DNA and then reacts covalently with the DNA; various ultimate carcinogens may be of this type. The utility of a set of bacterial strains for detecting carcinogens as mutagens is shown.Various planar polycyclic aromatic compounds, such as the acridines, which can intercalate in the DNA base-pair stack (1-9), are mutagens that cause additions or deletions of nucleotides (10-12). These errors appear to result from stabilization of a shifted pairing in a repetitive sequence in DNA by intercalation of the planar compound and subsequent addition or deletion of base pairs during replication or repair synthesis (11,13). Mlutagens with this property are called frameshift mutagens because of the shift in the reading frame of the mRNA synthesized from the altered DNA template; thus they differ from mutagens that cause basepair substitutions (11). The potency of an intercalating agent as a frameshift mutagen may increase by 10-to 100-fold if it also contains a side chain that can react covalently with DNA (12,(14)(15)(16)(17).Since it seemed possible that the reactive forms of some carcinogens with planar ring systems could be frameshift mutagens that both intercalate and react with DNA, epoxides of polycyclic hydrocarbons were examined and found to be mutagens of this type (16). In this paper this question is examined further with certain known and potential metabolites of 2-acetylaminofluorene (18). The striking activity of 2-nitrosofluorene as a frameshift mutagen then led to tests of nitroso derivatives related to various other aromatic amine carcinogens. These studies have made use of a set of tester strains (14-16) of Salmonella typhimurium that were developed for detection and classification of mutagens. MATERIALS AND METHODSBacterial Test for Mutagens. The mutagenicity test uses four Salmonella strains that require histidine (14-16). The test measures the effect of a mutagen on the reversion to growth on a histidine-free medium of these tester strains. Three of the tester strains (TA1531, TA1532, and TA1534) were designed for detecting frameshift mutagens with different specificities; each strain has a frameshift mutation in one of the genes of the histidine operon. The fourth strain (TA1530) has a base-pair change in the histidine G gene, and is used to detect mutagens that cause base-pair substitutions. In addition, all four strains lack the excision repair system (because of a deletion through uvrB); this makes them much more sensitive to any mutagen that alters the DNA in a way that would normally be repai...

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Section: Resultsmentioning

confidence: 99%

Carcinogens as Frameshift Mutagens: Metabolites and Derivatives of 2-Acetylaminofluorene and Other Aromatic Amine Carcinogens

Ames

Gurney

Miller

et al. 1972

Proc. Natl. Acad. Sci. U.S.A.

302

121

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“…In addition, it has no mutagenic, teratogenic or carcinogenic effects in animals (D. Lorke: personal communication). Therefore, metrifonate appears to be not only a suitable alternative to, but also has a considerably lower risk-to-benefit ratio than a widely used antischistosomal compound, hycanthone, whose mutagenic properties have been demonstrated in bacterial and mammalian cell systems in vitro (Hartman, Levine, Hartman & Berger, 1971;Clive, Flamm & Machesko, 1972), as well as in a host-mediated mammalian cell assay (G. A. Fischer: personal communication) and which has been found to be teratogenic in mice (Moore, 1972). These factors should receive especial attention when the treatment of urinary schistosomiasis is considered for children and other individuals with a long life expectancy.…”

Section: Discussionmentioning

confidence: 99%

Inhibition by metrifonate and dichlorvos of cholinesterases in schistosomes

Bueding

Liu

Rogers

1972

British J Pharmacology

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Summary1. No species differences between Schistosoma haematobium and Schistosoma mansoni were detected when the 150 of metrifonate for the acetylcholinesterases (AChE) and the cholinesterases (ChE) of these two trematodes were determined in isolated enzyme preparations or following exposure of the intact worms to this drug in vitro. 2. S. haematabium appeared to be more affected by AChE inhibition because, after administration of metrifonate to hamsters, a hepatic shift of the parasites was observed with a dose of metrifonate (150 mg (0-6 mmol) per kg) which produced no shift of S. mansoni, although AChE inhibition was comparable in both species. 3. Administration of a possible metabolite of metrifonate, dichlorvos, to hamsters resulted in a greater inhibition of AChE and ChE activities of S. haematobium than those of S. mansoni. Furthermore, when schistosomes were incubated with dichlorvos, inhibition of AChE activity of female S. haematobium was significantly greater (P<0 005) than that of both sexes of S. mansoni and of male S. haematobium. 4. The discrepancy between the lack of a significant chemotherapeutic effect of metrifonate in hamsters infected with S. haematobium and the clinical results obtained with this organophosphorus compound in human schistosomiasis haematobium is discussed, and the need to conduct similar studies in primates is pointed out.

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“…Revertants of this 305S strain were induced by spotting a drop of mutagen solution on enriched minimal agar spread plates by the method of Ames (2). The following carcinogens were used: 2-nitrosofluorene (NF) synthesized by Bartsch and Miller (3) and furnished by Ames; hycanthone (HC) (12,13), furnished by P. E. Hartman; nitroquinoline-N-oxide (NQ), furnished by H. B. Wood; and N-methyl-N'-nitro-N-nitrosoguanidine (NG) from Aldrich Chemicals.…”

Section: Methodsmentioning

confidence: 99%

Chemical Carcinogens as Frameshift Mutagens: Salmonella DNA Sequence Sensitive to Mutagenesis by Polycyclic Carcinogens

Isono

Yourno

1974

Proc. Natl. Acad. Sci. U.S.A.

138

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Other investigators have shown that several polycyclic carcinogens are frameshift mutagens in Salmonella. Mutagenic potency of these compounds is assessed by ability to induce reversion of histidine-requiring frameshift mutants to prototrophy. One frameshift mutation in the histidinol dehydrogenase gene, hisD3052, is unusually sensitive to mutagenesis by certain polycyclic carcinogens. We find that the 3052 mutation is a -1 deletion, probably loss of a G C pair from a DNA repeat of -G-G-G--C-C-C-. The polycyclic carcinogens tested (e.g., 2-nitroso- Frameshift mutations result from additions (+) or deletions (-) of DNA base pairs from genes encoding polypeptide chains, so that triplets in the product mRNA are not read in the correct frame after the mutation (7,8). Correction of such mutations may occur by restoration of the original base sequence, or by introduction of a closely positioned frameshift of opposite sign. In these double frameshift mutants (+ -) the normal reading frame is restored in mRNA except for the segment between the two frameshifts. The (+ -) mRNA segment encodes a segment of altered amino acids in the polypeptide chain, often disturbing its function. Sequencing the affected polypeptide segment allows reconstruction of associated mRNA and DNA sequences (9, 10). The hisD gene encodes the enzyme histidinol dehydrogenase (EC 1.1.1.23). To determine nucleic acid base changes in 3052 caused by polycyclic carcinogens and other frameshift mutagens, we have induced reversion in 3052 by these compounds. Revertants carrying double frameshift mutations were detected by rapid screening of crude extracts from revertants for altered histidinol dehydrogenase. The altered enzyme from each double mutant was then purified and compared with the normal enzyme by peptide mapping to detect altered peptides. These were sequenced to reconstruct altered DNA sequences in 3052 and its revertants. We have also classified the reversions with respect to certain properties of histidinol dehydrogenase from crude extracts, and have correlated the classes of reversion with specific DNA sequence changes.We believe that this newly characterized tester system will be useful for rapid screening of carcinogens as frameshift mutagens. For the relatively small effort of inducing reversions in 3052 with carcinogens or other mutagens and examining crude extract histidinol dehydrogenase, it should be possible to assign the reversions to the standard groups with known base sequence changes in DNA (see below).

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Hycanthone: A Frameshift Mutagen

Cited by 146 publications

References 24 publications

Carcinogens as Frameshift Mutagens: Metabolites and Derivatives of 2-Acetylaminofluorene and Other Aromatic Amine Carcinogens

Carcinogens as Frameshift Mutagens: Metabolites and Derivatives of 2-Acetylaminofluorene and Other Aromatic Amine Carcinogens

Inhibition by metrifonate and dichlorvos of cholinesterases in schistosomes

Chemical Carcinogens as Frameshift Mutagens: Salmonella DNA Sequence Sensitive to Mutagenesis by Polycyclic Carcinogens

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