Reversions, mutations and

Endosulfan is toxic to yeast but is also mutagenic without activation (Yadav et al. 1982). In vitro, endosulfan induced reverse mutations and mitotic gene conversion and increased the percentage of aberrant colonies in Saccharomyces cerevisiae but did not induce mitotic cross-overs (Yadav et al. 1982). 

As previously summarized, diethyl sulfate induced mutation and DNA damage in bacteria and induced reverse mutation and mitotic recombination in yeast. In plant cells, diethyl sulfate induced chromosomal aberrations. In a single study, diethyl sulfate did not induce heritable translocation in Drosophila melanogaster but did induce autosomal recessive lethal mutations, sex-linked recessive lethal mutations and genetic crossing-over. In cultured mammalian cells, diethyl sulfate induced chromosomal aberrations, mieronueleus formation, sister chromatid exchanges, forward mutation and DNA singlestrand breaks it also induced unscheduled DNA synthesis in primary cultures of rat... 

Singh I. 1983. Induction of reverse mutation and mitotic gene conversion by some metal compounds in Saccharomyces cerevisiae. MutatRes 117 149-152. 

The micronucleus assay is one type of study recommended by the FDA Redbook and ICH guidelines as part of a standard genetic toxicology battery. The other assays include the Ames (bacterial reverse mutation) and mouse lymphoma tests. 

Genetic toxicity testing follows the reconmiended test battery as outlined in Option 1 of ICH S2(R1), employing two in vitro assays (bacterial reversion mutation and chromosomal aberrations in hPBLs, +/- S9 metabolic activation) and the in vivo rat bone marrow micronucleus assay. Intracellular exposure to the full-length parent drug product has been demonstrated in all three assay systems (thereby applicable across different sequences). 

Sodium chlorite is not Hsted by the USEPA or any regulatory authority as a carcinogen. Studies conducted ia mice and rats did not show an increase in tumors in animals exposed to sodium chlorite in thek drinking water. Sodium chlorite has been found to have mutagenic activity in some in vitro test systems such as the Ames Salmonella reverse mutation assay without the presence of metaboHc activators. The significance of these test results in regard to human health is not clear because of the oxidizing effects of the chlorite ion (149). 

Physicochemical properties requked include melting/boiling point, vapor pressure, solubiUty, and flammabiUty/explosion characteristics. The toxicological studies include acute toxicity tests, oral, inhalation, and dermal skin and eye kritation skin sensiti2ation subacute toxicity, oral, inhalation, and dermal and mutagenicity tests. In vitro reverse mutation assay (Ames test) on Salmonella typhimurium and/or E.scherichia coli and mammalian cytogenic test. In vivo mouse micronucleus test. 

Escherichia coli (forward and reverse mutation) Gene mutation +/- No data Greim et al. 1975... 

Much toxicological data are available on this red pigment acute oral toxicity in mice, 90-day subchronic toxicological study, acute dermal irritation and corrosion, acute eye irritation and corrosion, anti-tumor effectiveness, micronucleus test in mice, AMES test Salmonella typhimurium reverse mutation assay), estimation of antibiotic activity, and results of estimation of five mycotoxins. A new patent on Arpink Red was filed in 2001 with claims of anti-cancer effects of the anthraquinone derivatives and apphcations in the food and pharmaceutical fields. 

Salmonella typhimurium (reverse mutation) Escherichia coli (forward mutation, DNA modification) Saccharomyces cerevisia (reverse mutation) Bacillus subtilis (rec assay) Gene mutation or DNA modification Bruce and Heddle 1979 Dunkel et al. 1984 Fukunaga et al. 1982 Kharab and Singh 1985 Nestmann et al. 1979 Nishioka 1975 Rosenkranz and Poirier 1979 Simmon 1979b... 

The human retrovirus HIV can be controlled using chemotherapy directed at the reverse transcriptase and aspartyl protease encoded by the viral genome as with other microbial pathogens, however, resistance to drug therapy becomes a major problem. Figure 7.3 shows a crystal structure (PDB 1HXW) of the HIV protease, where mutated amino acids (shown in cyan) lead to disrupted binding of the clinically effective inhibitor ritonavir [24]. 

UCW = capped water, TW = tethered water (see text), k = force constant for restraining potential (kcal/mol/A2). b Radius (A) of solvation sphere. 1 Numbers of dynamical water molecules within solvation sphere. d Mean and standard error for the forward (i.e. 8-methyl-N5-deazapterin —> 8-methylpterin) and reverse mutation of the electrostatic force field Cutoff for protein-ligand and solvent-ligand interaction all other interactions are subject to a 9 A cutoff. 

Macgregor, J.T., D.H. Gould, A.D. Mitchell, and G.P. Sterling. 1979. Mutagenicity tests of diflubenzuron in the micronucleus test in mice, the L5178Y mouse forward mutation assay, and the Ames Salmonella reverse mutation test. Mutat. Res. 66 45-53. 

Skin sensitization Ames test To determine the potential to induce skin sensitization reactions To evaluate potential mutagenic activity in a bacterial reverse mutation system with and without metabolic activation... 

In the bacterial mutation test, the mutagenic potential of a pharmaceutical and its metabolites is evaluated by measuring and quantifying its ability to induce reverse mutations at selected loci of Salmonella typhimurium or Escherichia coli in the presence and absence of metabolic activation. This test system has been shown to detect a diverse group of chemical mutagens.3,4 The technical details of this test have been reported in the literature.5-7... 

Genotypic resistance assays use DNA sequencing methods to examine the reverse transcriptase and protease regions of fhe HIV genome for all resistance-associated mutations. A major drawback of fhis fesfing mefhod is that results are difficult to interpret and expert consultation is necessary. 

---