Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.3.1.107 (DAT)
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Some compounds have structural isomers of which one is apparently carcinogenic, and the other not. Because of the similarity of their chemical structures, comparisons of their effects can allow gene expression elicited in response to the basic skeletons of the isomers to be disregarded. We compared the gene expression profiles of male Fischer 344 rats administered by daily oral gavage up to 28 days using an in-house oligo microarray. 2-Acetylaminofluorene (2-AAF), 2,4-diaminotoluene (2,4-DAT), 2-nitropropane (2-NP), and 2-nitro-p-phenylenediamine (2-NpP) are hepatocarcinogenic. However, their isomers, 4-acetylaminofluorene (4-AAF), 2,6-diaminotoluene (2,6-DAT), 1-nitropropane (1-NP), and 4-nitro-o-phenylenediamine (4-NoP), are non-hepatocarcinogenic. Because of the limited carcinogenicity of 2-NpP, we attempted to perform two-parametric comparison analyses with (1) a set of 4 isomers: 2-AAF, 2,4-DAT, 2-NP, and 2-NpP as "carcinogenic", and 4-AAF, 2,6-DAT, 1-NP, and 4-NoP as "non-carcinogenic"; and (2) a set of 3 isomers: 2-AAF, 2,4-DAT, and 2-NP, as "carcinogenic", and 4-AAF, 2,6-DAT, and 1-NP as "non-carcinogenic". After ratio filtering and Welch's approximate t-test analysis, 54 and 28 genes were selected from comparisons between the sets of 3 and 4 isomers, respectively, for day 28 data. Using hierarchical clustering analysis with the 54 or 28 genes, 2-AAF, 2,4-DAT, and 2-NP clustered into a "carcinogenic" branch. 2-NpP was in the same cluster as 4-NoP and 4-AAF. This clustering corresponded to the previous finding that 2-NpP is not carcinogenic in male Fischer 344 rats, which indicates that comparing the differences in gene expression elicited by different isomers is an effective method of developing a prediction system for carcinogenicity.
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PMID:Differences in gene expression profiles in the liver between carcinogenic and non-carcinogenic isomers of compounds given to rats in a 28-day repeat-dose toxicity study. 1707 Aug 81

One of the problems of in vitro genotoxicity testing is the inadequate representation of drug metabolizing enzymes in indicator cells which are currently used. An alternative are human derived liver cell lines which retained the activities of enzymes that catalyze the activation and detoxification of genotoxins. Several cell lines were identified which were used in comet experiments. The most frequently employed line is HepG2, i.e. more than 400 individual compounds have been tested; furthermore, it was also used for the detection of combined effects in mixtures as drug metabolizing and antioxidant enzymes are represented in inducible form. One of the shortcomings of these cells are the strong inter-laboratory variation of the results. Recently it was postulated that HepaRG cells are an ideal model for human liver studies, but comet experiments were only partly successful and failed to detect genotoxins such as cadmium chloride, styrene and etoposide, as well as compounds that require activation via N-actetyltransferases (IQ, 2,4-DAT, 2-AAF). Furthermore, these cells are relatively insensitive towards ROS. Hep3B cells were used in a few studies but failed to detect representatives of important genotoxic carcinogens (AFB1, B(a)P, NDMA, IQ, PhiP), the line HCC1.1 was sensitive towards these chemicals but possesses an instable karyotype and a mutated p53. A more promising line is Huh6, but further validation of the usefulness for routine testing is needed. Recent developments which may lead to a better metabolic capacity of liver cells include improvement of the growth conditions (e.g. increase of serum levels, use of differentiated cells and of 3D-cultures), use of differentiated stem cells with hepatocyte like characteristics or of transformed proliferating hepatocytes.
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PMID:Use of human derived liver cells for the detection of genotoxins in comet assays. 3156 85