Discrimination of genotoxic and non-genotoxic hepatocarcinogens by statistical analysis based on gene expression profiling in the mouse liver as determined by quantitative real-time PCR.

The general aim of the present study is to discriminate between mouse genotoxic and non-genotoxic hepatocarcinogens via selected gene expression patterns in the liver as analyzed by quantitative real-time PCR (qPCR) and statistical analysis. qPCR was conducted on liver samples from groups of 5 male, 9-week-old B6C3F(1) mice, at 4 and 48h following a single intraperitoneal administration of chemicals. We quantified 35 genes selected from our previous DNA microarray studies using 12 different chemicals: 8 genotoxic hepatocarcinogens (2-acetylaminofluorene, 2,4-diaminotoluene, diisopropanolnitrosamine, 4-dimethylaminoazobenzene, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, N-nitrosomorpholine, quinoline and urethane) and 4 non-genotoxic hepatocarcinogens (1,4-dichlorobenzene, dichlorodiphenyltrichloroethane, di(2-ethylhexyl)phthalate and furan). A considerable number of genes exhibited significant changes in their gene expression ratios (experimental group/control group) analyzed statistically by the Dunnett's test and Welch's t-test. Finally, we distinguished between the genotoxic and non-genotoxic hepatocarcinogens by statistical analysis using principal component analysis (PCA) of the gene expression profiles for 7 genes (Btg2, Ccnf, Ccng1, Lpr1, Mbd1, Phlda3 and Tubb2c) at 4h and for 12 genes (Aen, Bax, Btg2, Ccnf, Ccng1, Cdkn1a, Gdf15, Lrp1, Mbd1, Phlda3, Plk2 and Tubb2c) at 48h. Seven major biological processes were extracted from the gene ontology analysis: apoptosis, the cell cycle, cell proliferation, DNA damage, DNA repair, oncogenes and tumor suppression. The major, biologically relevant gene pathway suggested was the DNA damage response pathway, resulting from signal transduction by a p53-class mediator leading to the induction of apoptosis. Eight genes (Aen, Bax, Btg2, Ccng1, Cdkn1a, Gdf15, Phlda3 and Plk2) that are directly associated with Trp53 contributed to the PCA. The current findings demonstrate a successful discrimination between genotoxic and non-genotoxic hepatocarcinogens, using qPCR and PCA, on 12 genes associated with a Trp53-mediated signaling pathway for DNA damage response at 4 and 48 h after a single administration of chemicals.

The antimicrobial activity, toxicity and antimicrobial mechanism of a new type of tris(alkylphenyl)sulfonium.

The antimicrobial activity, toxicity and antimicrobial mechanism of a new type of tris(4-alkylphenyl)sulfonium which has sterically bulky alkyl substituents (bTAPS), were estimated and compared with those of other sulfoniums which we reported previously. Concerning tris {4-(iso-propyl)phenyl}sulfonium (bTAPS-iso3) and tris{4-(tert-butyl)phenyl}sulfonium (bTAPS-tert4), the antimicrobial activity of these compounds tended to be lower than both tri(n-alkyl)sulfoniums (TASs) and tris{4-(n-alkylphenyl)}sulfoniums (TAPSs) at similar ClogP values. However, the activities of tris{4-(cyclohexyl)phenyl}sulfonium (bTAPS-cyclo6) were clearly higher than those of TAS and were almost similar to those of TAPS at similar ClogP values. The mutagenicities of tested bTAPSs were judged to be all negative. Both the acute oral toxicity strength and the acute skin irritation/corrosion toxicity strength tended to follow the order of TAPSs > bTAPSs > TASs. However, only the acute skin irritation/corrosion toxicity strength of bTAPS-cyclo6 was almost as low as that of TAS which has a similar ClogP value to bTAPS-cyclo6. Because bTAPS-cyclo6 has both high antimicrobial activity and low toxicity, this compound might become to be an alternative antimicrobial compound to relatively hazardous antimicrobials which have been widely used in many fields.

The antimicrobial activity, hydrophobicity and toxicity of tri(n-alkyl)sulfoniums and tris(n-alkylphenyl) sulfoniums, and their relationships.

The antimicrobial activity, hydrophobicity and toxicity of tri(n-alkyl)sulfoniums (TASs) and tris{4-(n-alkylphenyl)}sulfoniums (TAPSs), and their relationships were investigated. The antimicrobial activity against the tested strains tended to increase with the increase in the sulfonium ClogP between 7 and approximately 12 and beyond that decreased with the increase in the ClogP in both sulfoniums. The antimicrobial activities of the most TAPSs were higher than those of the TASs at similar ClogP values. The mutagenicity of the TASs and the TAPSs was judged to be negative. The acute oral toxicity decreased with the increase in the ClogP in the both sulfoniums. The skin irritation/corrosion increased with the increase in the ClogP between approximately 7 and 12, and beyond that decreased or similar with the increase in the ClogP in both sulfoniums. It is noted that the acute toxicity and the skin irritation/corrosion of the TAPSs were clearly higher than those of the TASs at a similar ClogP. In comparing the sulfoniums to representative quaternary ammonium compounds (QACs), the antimicrobial activities of the some sulfoniums were higher than those of QACs and the toxicity was lower. Therefore, some sulfoniums could be utilized in many fields instead of the presently and widely-used QACs.

The antimicrobial activity, hydrophobicity and toxicity of sulfonium compounds, and their relationship.

The sulfonium compound is a kind of cationic surfactant as well as a quaternary ammonium which has been used widely around the globe. This study investigated the antimicrobial activity, the hydrophobicity, the toxicity of several sulfoniums and their relationship with the aim of clarifying their antimicrobial activity and toxicity, and, furthermore, of predicting their usefulness availability as antimicrobials. As a result, the antimicrobial activity, expressed as the minimum inhibitory concentration (MIC) of the sulfoniums examined in this study, tended to decrease with the increase of their hydrophobicity, estimated by ClogP, and their antimicrobial activity against the gram-positive bacteria was higher than that against the gram-negative bacteria used in this study. The antimicrobial activities of several sulfoniums against the gram-positive bacteria were higher than those of some common cationic antimicrobials including quaternary ammoniums such as cetylpyridinium chloride (CPC) and benzalkonium chloride (BKC). In contrast, the antimicrobial activities of the sulfoniums against the gram-negative bacteria were lower than those of some common cationic antimicrobials. Meanwhile the toxicity, in particular, the acute dermal irritation/corrosion of the sulfoniums, tended to be lower than that of common cationic antimicrobials which were toxic in many cases indices. These results suggest that the sulfoniums might become useful antimicrobials which are less hazardous to human health than common cationic antimicrobials.