臺灣博碩士論文加值系統

此次的研究使用氧電極偵測假單胞菌(ATCC 23973)在不同濃度的甲苯芳香族系列化合物之下對苯甲酸鈉的耗氧初始速率，而得到各化合物的Ki值。並由此Ki值去評估各種甲苯芳香族系列化合物的毒性大小。結果發現，化合物毒性隨著甲烷取代基增加而毒性上升，氯取代基也是如此。而甲苯芳香族化合物系列中，以苯胺系列毒性最小，酚次之。另外，假單胞菌可降解苯甲醛、苯甲酸系列化合物，其中以苯甲醛系列化合物尤其明顯。
此次的研究我們以logKi對MlogP及Elumo作迴歸分析，得到一個方程式：log1/Ki=－0.35(±0.04)ELUMO+0.35(±0.036)MlogP-1.98(±0.1)，R2=0.808；而在去除三點偏離點後，得到一個最佳公式：log1/Ki =－0.36 (±0.032 )ELUMO + 0.37 (±0.030) MlogP -2.04 (±0.078)；n = 42，R2 = 0.8889。

Acute toxicity of toluene series to Pseudomonas putida(ATCC 23973)was estimated by an initial oxygen uptake method. Inhibition studies of these compounds on the oxidation of benzoate by Pseudomonas putida were expressed as oxygen uptake rates.Double reciprocal plots for the inhibition by these compounds of oxygen uptake in Pseudomonas,a physical constant(Ki) was obtained.
Pseudomonas putida can degrade Benzaldehyde and Benzoic acid series compound. In toluene series,compound with NH2- and OH-substituent were found less toxicity than other substituted toluenes.
In this study,in correlation of log(1/Ki) with logP(logarithm of 1-octanol-water partition coefficient ) and LUMO(lowest unoccupied molecular orbital),the following one equation were obtained.
log1/Ki =－0.36 (±0.032 )ELUMO+0.37 (±0.030) MlogP -2.04 (±0.08)
n = 42，R2 = 0.8889，s = 0.15，F = 152.09

誌謝-------------------------------------------------------------------------Ⅰ
中文摘要---------------------------------------------------------------------Ⅲ
英文摘要---------------------------------------------------------------------Ⅳ
目錄-------------------------------------------------------------------------Ⅴ
表目錄-----------------------------------------------------------------------Ⅶ
圖目錄-----------------------------------------------------------------------Ⅷ
第一章緒論---------------------------------------------------------------1
一、生物方法應用於毒性評估-----------------------------------------1
二、利用生物測試化合物毒性的方法-----------------------------------2
三、假單胞菌的簡介-------------------------------------------------8
四、甲苯的降解途徑-------------------------------------------------8
五、結構-活性定量關係----------------------------------------------9
六、實驗目的------------------------------------------------------13
第二章實驗--------------------------------------------------------------14
一、藥品----------------------------------------------------------14
二、儀器----------------------------------------------------------16
三、實驗內容------------------------------------------------------17
第三章結果--------------------------------------------------------------33
一、生物可降解(degrade)化合物的類型-------------------------------34
二、競爭型抑制(Competitive inhibition)模式------------------------36
三、非競爭型抑制模式(Noncompetitive inhibition)及偏離點(Outlier) -36
四、化合物毒性與構造關係------------------------------------------41
第四章結論--------------------------------------------------------------44
參 考 文 獻----------------------------------------------------------------45
附 錄----------------------------------------------------------------49

1.Akersa, K. S., G. D. Sinks, and T. W. Schultz. Structure—toxicity relationships for selected halogenated aliphatic chemicals. Environ. Toxicol. and Pharmacol. 7:33-39, 1999.
2.Basak, S. C., B. D. Gute, B. Luc, and S. N. N. Trinajstic. A comparative QSAR study of benzamidines complement—inhibitory activity and benzene derivatives acute toxicity. Computers and Chemistry 24:181—191, 2000.
3.Bearden, A. P., G. D. Sinks, W. H. J. Vaes, E. U. Ramos,
J. L. M. Hermens, and T. W. Schultz. Bioavailability, Biodegradation, and Acclimation of Tetrahymena pyriformis to 1-Octanol. Ecotoxicol. and Environ. Safety 44:86-91,1999.
4.Bearden, A. P., and T. W. Schultz. Struvture-Activity Relationships For Pimephales and Tetrahymena：A Mechanism of Action Approach. Environmental Toxicology and Chemistry 16:1311—1317, 1997.
5.Cottrell, M. B., and T. W. Schultz. Structure—Toxicity Relationships for Methyl Esters of Cyanoacetic Acids to Tetrahymena pyriformis. Bull. Environ. Contam. Toxicol. 70:549—556, 2003.
6.Cronin, M. T. D., A. O. Aptula, C. D. Judith, T. I. Netzeva, P. H. Rowe, I. V. Valkova, and T. W. Schultz. Comparative assessment of methods to develop QSARs for the prediction of the toxicity of phenols to Tetrahymena pyriformis. Chemosphere 49 : 1201-1221, 2002.
7.Cronin, M. T. D., B. W. Gregory, and T. W. Schultz. Quantitative Structure-Activity Analyses of Nitrobenzene Toxicity to Tetrahymena pyriformis Chem. Res. Toxicol. 11:902-908, 1998.
8.Cronin, M. T. D., and T. W. Schultz. Structure-Toxicity Relationships for Phenols To Tetrahymena pyriformis. Chemosphere. 32:1453-1468, 1996.
9.Cronin, M. T. D., and T. W. Schultz. Structure—Toxicity Relationships for Three Mechanisms of Action of Toxicity to Vibrio fischeri. Ecotoxicol. and Environ. Safety 39: 65—69, 1998.
10.Cronin, M. T. D., and T. W. Schultz. Development of Quantitative Structure-Activity Relationships for the Toxicity of Aromatic Compounds to Tetrahymena pyriformis: Comparative Assessment of the Methodologies. Chem. Res. Toxicol.14: 1284-1295, 2001.
11.Gibson, D.T., M. Hensley, H. Yoshioka, and T.J. Mabry.
Formation of (+)-cis-2,3-dihydroxy-1-methylcyclohexa-4,6-diene from toluene by Pseudomonas putida. Biochemistry. 9:1626—1630, 1970.
12.Johnson, C. D.The Hammett equation-(Cambridge texts in Chemistry and Biochemistry),Elmore,D.T., J.Lewis,；K.Schofield, D.Sc.and ,J.M.Thomas, Eds.,London,1980.
13.Lewis, D. F. V. A Quantitative Structure-Activity Relationship study On a series of 10 para-substituted toluenes binding to Cytochrome P4502B4(CYP2B4),and their hydroxylation rates.Biochemical Pharmacol:50,619-625, 1995.
14.McFarland, J. W. On the parabolic relationship between drug potency and hydrophobicity. J. Med. Chem. 13:1092—1196, 1970.
15.Mekapati, S. B. and C. Hansch. On the Parametrization of the Toxicity of Organic Chemicals to Tetrahymena pyriformis.The Problem of Establishing a Uniform Activity. J. Chem. Inf. Comput. Sci. 42:956-961, 2002.
16.Niculescu, S. P., K. L. E. Kaiser., and T. W. Schultz. Modeling the Toxicity of Chemicals to Tetrahymena pyriformis Using Molecular Fragment Descriptors and Probabilistic Neural Networks. Arch. Environ. Contam. Toxicol. 39:289—298, 2000.
17 Ramos, E. U., W. H. J. Vaes, P. Mayer, and J. L.M. Hermens.Algal growth inhibition of Chlorella pyrenoidosa by polar narcotic pollutants: toxic cell concentrations and QSAR modeling. Aquatic Toxicol:46,1—10, 1999.
18.Ren, S. Predicting three narcosis mechanisms of aquatic toxicity. Toxicol Letters 133:127—139, 2002.
19.Ren, S., and T. W. Schultz. Identifying the mechanism of aquatic toxicity of selected compounds by hydrophobicity and electrophilicity descriptors. Toxicol Letters:129,151—160, 2002.
20.Schultz, T. W. Structure-Toxicity Relationships for Benzenes Evaluated with Tetrahymena pyriformis. Chem. Res. Toxicol.12: 1262-1267,1999.
21.Schultza, T. W., M. T. D. Cronin, and T. I. Netzeva. The present status of QSAR in toxicology. Journal of Molecular Structure 622:23-28, 2003.
22.Schultz, T. W., S. E. Bryant, and T. S. Kissel. Toxicological Assessment in Tetrahymena of Intermediates in Aerobic Microbial Transformation of Toluene and p-Xylene. Bull. Environ. Contam. Toxicol. 56:129-134, 1996.
23.Schultz, T.W., G.D. Sinks, and A. P. Bearden. QSARs in aquatic toxicology: a mechanism of action approach comparing toxic potency to Pimephales promelas, Tetrahymena pyriformis and Vibrio .scheri. In: J. Devillers,(Ed) Comparative QSAR. Taylor and Francis, London, pp. 51-109, 1998.
24 Schultz, T. W., and V. A. Tucker. Structure-Toxicity Relationships for the Effects of N- and N,N_-Alkyl Thioureas to Tetrahymena pyriformis. Bull. Environ. Contam. Toxicol. 70:1251—1258, 2003.
25.Seward, J. R., E. L. Hamblen, and T. W. Schultz. Regression comparisons of Tetrahymena pyriformis and Poecilia reticulata toxicity. Chemosphere 47:93-101, 2002.
26.Seward, J. R., G. D. Sinks, and T. W. Schultz. Reproducibility of toxicity across mode of toxic action in the Tetrahymena population growth impairment assay. Aquatic Toxicology 53:33—47, 2001.
27.Sixt, S., Quantitative Structure-Toxicity Relationship For 80 Chlorinated Compounds Using Quantum Chemical Descriptors. Chemosphere:30,2397-2414, 1995.
28.Todd, M. M., and D. M. Young. Prediction of the Acute Toxicity (96-h LC50) of Organic Compounds to the Fathead Minnow (Pimephales promelas) Using a Group Contribution Method. Chem. Res. Toxicol.14:1378-1385, 2001.
29.Wackett, L.P., L.D. Kwart, and D.T. Gibson. Benzylic
monooxygenation catalyzed by toluene dioxygenase from Pseudomonas putida. Biochemistry. 27:1360—1367, 1988.
30.Weber, F.J., K. C. Hage, and J. A. M. De Bont. Growth of the Fungus Cladosporium sphaerospermum with Toluene as the Sole Carbon and Energy Source. .Applied and Environ. Microbiol.:61, 3562—3566, 1995.
31.駱尚廉主編,環境保護辭典,中華民國環境工程學會,1997.
32.環境檢驗所檢測方法網站,
http://www.niea.gov.tw/analysis/method/m_t.asp
33.劉惠雲,氯酚與細菌反應的研究,國立成功大學化學系碩士論文, 1991.
34.林淑茹,芳香族化合物對假單胞菌之瞬時毒性與化合物結構關係
之研究,國立成功大學化學系碩士論文,1999.