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Mutagenic Potential (mutagenic + potential)

Distribution by Scientific Domains

Life Sciences	50%

Selected Abstracts

Assessment of the sensitivity of the computational programs DEREK, TOPKAT, and MCASE in the prediction of the genotoxicity of pharmaceutical molecules

ENVIRONMENTAL AND MOLECULAR MUTAGENESIS, Issue 3 2004
Ronald D. Snyder
Abstract Computational models are currently being used by regulatory agencies and within the pharmaceutical industry to predict the mutagenic potential of new chemical entities. These models rely heavily, although not exclusively, on bacterial mutagenicity data of nonpharmaceutical-type molecules as the primary knowledge base. To what extent, if any, this has limited the ability of these programs to predict genotoxicity of pharmaceuticals is not clear. In order to address this question, a panel of 394 marketed pharmaceuticals with Ames Salmonella reversion assay and other genetic toxicology findings was extracted from the 2000,2002 Physicians' Desk Reference and evaluated using MCASE, TOPKAT, and DEREK, the three most commonly used computational databases. These evaluations indicate a generally poor sensitivity of all systems for predicting Ames positivity (43.4,51.9% sensitivity) and even poorer sensitivity in prediction of other genotoxicities (e.g., in vitro cytogenetics positive; 21.3,31.9%). As might be expected, all three programs were more highly predictive for molecules containing carcinogenicity structural alerts (i.e., the so-called Ashby alerts; 61% ± 14% sensitivity) than for those without such alerts (12% ± 6% sensitivity). Taking all genotoxicity assay findings into consideration, there were 84 instances in which positive genotoxicity results could not be explained in terms of structural alerts, suggesting the possibility of alternative mechanisms of genotoxicity not relating to covalent drug-DNA interaction. These observations suggest that the current computational systems when applied in a traditional global sense do not provide sufficient predictivity of bacterial mutagenicity (and are even less accurate at predicting genotoxicity in tests other than the Salmonella reversion assay) to be of significant value in routine drug safety applications. This relative inability of all three programs to predict the genotoxicity of drugs not carrying obvious DNA-reactive moieties is discussed with respect to the nature of the drugs whose positive responses were not predicted and to expectations of improving the predictivity of these programs. Limitations are primarily a consequence of incomplete understanding of the fundamental genotoxic mechanisms of nonstructurally alerting drugs rather than inherent deficiencies in the computational programs. Irrespective of their predictive power, however, these programs are valuable repositories of structure-activity relationship mutagenicity data that can be useful in directing chemical synthesis in early drug discovery. Environ. Mol. Mutagen. 43:143,158, 2004. © 2004 Wiley-Liss, Inc. [source]

The use of toxicity bioassays to monitor the recovery of oiled wetland sediments

ENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 9 2003
Danica C. Mueller
Abstract Six toxicity assays were compared to determine their efficacy in assessing toxicity dynamics during a wetland bioremediation study. The toxicity bioassays used were the Microtox® 100% elutriate test, Microtox Solid Phase Test (SPT), amphipod assay, P450 reporter gene system, Toxi-ChromoPadÔ test and a Salmonella/microsome assay. Oiled sediments were analyzed for toxicity in the petroleum biostimulation experiment conducted along the San Jacinto River, near Houston (TX, USA). The bioassays were evaluated for their ability to measure acute toxicity, chronic toxicity, and the mutagenic potential of amended oiled plots as compared to oiled and unoiled control plots. Amendments were diammonium phosphate alone or in combination with potassium nitrate, which served as an alternate electron acceptor. With exception of the Toxi-ChromoPad and Salmonella tests, the bioassays exhibited a significant increase in toxicity after oil application. Microtox bioassays detected significant sediment toxicity up to 29 d after oil and amendment application. The Microtox solid phase test results correlated strongly with gas chromatographymass spectrometry analyses of total target saturate and aromatic hydrocarbons. The amphipod assay detected initial toxicity with a decline to day 70, followed by a significant increase in toxicity on day 140 in plots receiving nutrient amendments, which may be in response to excessive nutrient application. Low levels of enzyme induction were observed with the P450 reporter gene system assay in all oiled sediments throughout the study, suggesting low but persistent levels of polycyclic aromatic hydrocarbons. Of the six tests, the two Microtox tests and the amphipod test showed the most potential in evaluating petroleum toxicity in wetland sediments. [source]

MUTYH mutations associated with familial adenomatous polyposis: functional characterization by a mammalian cell-based assay,

HUMAN MUTATION, Issue 2 2010
Sara Molatore
Abstract MUTYH -associated polyposis (MAP) is a colorectal cancer syndrome, due to biallelic mutations of MUTYH. This Base Excision Repair gene encodes for a DNA glycosylase that specifically mitigates the high mutagenic potential of the 8-hydroxyguanine (8-oxodG) along the DNA. Aim of this study was to characterize the biological effects, in a mammalian cell background, of human MUTYH mutations identified in MAP patients (137insIW [c.411_416dupATGGAT; p.137insIleTrp]; R171W [c.511C>T; p.Arg171Trp]; E466del [c.1395_1397delGGA; p.Glu466del]; Y165C [c.494A>G; p.Tyr165Cys]; and G382D [c.1145G>A; p.Gly382Asp]). We set up a novel assay in which the human proteins were expressed in Mutyh,/, mouse defective cells. Several parameters, including accumulation of 8-oxodG in the genome and hypersensitivity to oxidative stress, were then used to evaluate the consequences of MUTYH expression. Human proteins were also obtained from Escherichia coli and their glycosylase activity was tested in vitro. The cell-based analysis demonstrated that all MUTYH variants we investigated were dysfunctional in Base Excision Repair. In vitro data complemented the in vivo observations, with the exception of the G382D mutant, which showed a glycosylase activity very similar to the wild-type protein. Our cell-based assay can provide useful information on the significance of MUTYH variants, improving molecular diagnosis and genetic counseling in families with mutations of uncertain pathogenicity. Hum Mutat 30:1,8, 2009. © 2009 Wiley-Liss, Inc. [source]

Efficacy and Safety Evaluation of Ozonation to Degrade Aflatoxin in Corn

JOURNAL OF FOOD SCIENCE, Issue 8 2002
A.D. Prudente Jr.
ABSTRACT: This study determined the efficacy and safety of ozonation in degrading aflatoxin in corn. Ozonation (10 to 12 wt%) reduced aflatoxin levels by 92% and no reversion to the parent compound was observed. Ozonation had minimal effect on fatty acids of uncontaminated corn, but had significant effect on fatty acids of contaminated corn. Crude extracts showed no mutagenic potential in the Ames assay using TA98 and TA100. Clean-up using hexane increased their mutagenic potentials. Clean-up using Mycosep columns increased the mutagenic potentials 18 to 617%. Hexane extracts from ozone-treated contaminated corn had lower inhibitory effect. This suggested that a fat-soluble mutagen is being formed or natural inhibitors of mutagenicity are being destroyed. [source]

Carcinogenesis in reflux disease,In search for bile-specific effects

MICROSURGERY, Issue 8 2007
M.D., Martin Fein Ph.D.
Bile reflux may play a key role for esophageal carcinogenesis in reflux disease. In search for bile-specific effects, the animal model of esophageal cancer was applied in a mutagenesis assay. Big Blue® transgenic mice were operated with microsurgical techniques. Seven had total gastrectomy with esophagojejunostomy creating esophageal reflux of bile and five had a sham operation. After 24 weeks, the mutation frequency (MF) was measured through standard Big Blue mutagenesis assay in the esophageal mucosa and the duodenum as control. Esophageal reflux resulted in esophagitis in the distal esophagus. The MF in esophageal mucosa was 1.6 times higher in animals with reflux than in sham-operated animals; it was identical in the duodenum. In conclusion, the mutagenic potential of bile reflux has been confirmed. However, mechanisms of carcinogenesis in the esophageal cancer model other than chronic inflammation could not be identified because of the only moderately increased MF. © 2007 Wiley-Liss, Inc. Microsurgery, 2007. [source]