In silico toxicological screening of natural products

Toxicology Mechanisms and Methods

Volumn 18, Issue 2-3, 2008, Pages 229-242

  Arvidson, Kirk B ^a   Valerio Jr , Luis G ^a   Diaz, Marilyn ^b   Chanderbhan, Ronald F ^a  

^a CENTER FOR DRUG EVALUATION AND RESEARCH   (United States)

^b UNIVERSITY OF PUERTO RICO   (Puerto Rico)

Author keywords

Botanicals; Cancer; Carcinogenicity; Computational Toxicology; Dietary Chemicals; In Silico; Mechanisms; Natural Products; QSAR; Rodents; SAR; Structure Activity Relationship; Toxicity Prediction

Indexed keywords

ARISTOLOCHIC ACID; EPICATECHIN; ESTRAGOLE; NATURAL PRODUCT; OCTACOSANOL; PULEGONE; THIOCTIC ACID;

ARTICLE; CHEMICAL MODEL; COMPUTER MODEL; COMPUTER PROGRAM; DATA MINING; DIET; EXPERIMENTAL STUDY; EXPOSURE; HUMAN; METABOLISM; NONHUMAN; PREDICTION; PRIORITY JOURNAL; SCREENING; TOXICOLOGY; VALIDITY;

RODENTIA;

EID: 40949128736     PISSN: 15376516     EISSN: 15376524     Source Type: Journal    
DOI: 10.1080/15376510701856991     Document Type: Article

References (115)

1. Abshear, T., Banik, G. M., D'Souza, L., Nedwed, K., and Peng, C. 2006. A model validation and consensus building environment. SAR QSAR Environ. Res. 17(3):311-321.
2. Adhikari, P., Hwang, K. T., Park, J. N., and Kim, C. K. 2006. Policosanol content and composition in perilla seeds. J. Agric. Food Chem. 54:5359-5362.
3. Aggarwal, B. B., and Shishodia, S. 2006. Molecular targets of dietary agents for prevention and therapy of cancer. Biochem. Pharmacol. 71:1397-1421.
4. Aleman, C. L., Mas Ferreiro, R., Nao Puig, M., Rodeiro, G. I., Hernandez, O. C., and Capote, A. 1994. Carcinogenicity of policosanol in Sprague Dawley rats: a 24 month study. Teratog. Carcinog. Mutagen. 14:239-249.
5. Aleman, C. L., Puig, M. N., Elias, E. C., Ortega, C. H., Guerra, I. R., Ferreiro, R. M., and Brinis, F. 1995. Carcinogenicity of policosanol in mice: an 18-month study. Food Chem. Toxicol. 33:573-578.
6. Ames, B. N., and Gold, L. S. 1998. The prevention of cancer. Drug. Metab. Rev. 30(2): 201-223.
7. Anthony, A., Caldwell, J., Gutt, A. J., and Smith, R. L. 1987. Metabolism of estragole in rat and mouse and influence of dose size on excretion of the proximate carcinogen 1′-hydroxyestragole. Food Chem. Toxicol. 25(11):799-806.
8. Arlt, V. M., Stilborova, M., and Schmeiser, H. H. 2002. Aristolochic acid as a probably human cancer hazard in herbal remedies: a review. Mutagenesis 17:265-277.
9. Arruzazabala, M. L., Carbajal, D., Mas, R., Molina, V., Valdes, S., and Laguna, A. 1994. Cholesterol-lowering effects of policosanol in rabbits. Biol. Res. 27:205-208.
10. Ashby, J., and Tennant, R. W. 1991. Definitive relationships among chemical structure, carcinogenicity and mutagenicity for 301 chemicals tested by the U.S. NTP. Mutat. Res. Rev. Genet. Toxicol. 257(3):229-306.
11. Bailey, A. B., Chanderbhan, R., Collazo-Braier, N., Cheeseman, M. A., and Twaroski, M. L. 2005. The use of structure-activity relationship analysis in the food contact notification program. Regul. Toxicol. Pharmacol. 42(2):225-235.
12. Banik, G. M. 2004. In silico ADME-Tox prediction: the more, the merrier. Curr. Drug Discov. 4:31-34.
13. Bilska, A., and Wlodek, L. 2005. Lipoic acid- the drug of the future?. Pharmacol Reports 57:570-577.
14. Blower, P. E., Cross, K. P., Eicher, G. S., Myatt, G. J., Weinstein, J. N., and Yang, C. 2006. Comparison of methods for sequential screening of large compound sets. Comb. Chem. High Throughput Screen. 9(2):115-122.
15. Boyer, J., and Liu, R. H. 2004. Apple phytochemicals and their health benefits. Nutr. J. 3(5):1-15.
16. Bugrim, A., Nikolskaya, T., and Nikolsky, Y. 2004. Early prediction of drug metabolism and toxicity: systems biology approach and modeling. Drug Discov. Today 9(3):127-135.
17. Buschman, J. L. 1998. Green tea and cancer in humans: a review of the literature. Nutr. Cancer 31:151-159.
18. Bustamante, J., Lodge, J. K., Marcocci, L., Tritschler, H. J., Packer, L., and Rihn, B. H. 1998. Alpha-lipoic acid in liver metabolism and disease. Free Radic. Biol. Med. 24(6):1023-1039.
19. Chen, L. J., Lebetkin, E. H., and Burka, L. T. 2001. Metabolism of R-(+)-pulegone in F344 rats. Drug Metab. Dispos. 29:1567-1577.
20. Cheng, Y., Wang, Y., and Wang, X. 2006. A causal relationship discovery-based approach to identifying active components of herbal medicine. Comput. Biol. Chem. 30(2):148-154.
21. Chou, F. P., Chu, Y. C., Hsu, J. D., Chiang, H. C., and Wang, C. J. 2000. Specific induction of glutathione S-transferase GSTM2 subunit expression by epigallocatechin gallate in rat liver. Biochem. Pharmacol. 60:643-650.
22. Contrera, J. F., Kruhlak, N. L., Matthews, E. J., and Benz, R. D. 2007. Comparison of MC4PC and MDL-QSAR rodent carcinogenicity predictions and the enhancement of predictive performance by combining QSAR models. Regul. Toxicol. Pharmacol. July 17;49(3):172-182.
23. Contrera, J. F., Maclaughlin, P., Hall, L. H., and Kier, L. B. 2005. QSAR modeling of carcinogenic risk using discriminant analysis and topological molecular descriptors. Curr. Drug. Discov. Technol. 2(2):55-67.
24. Contrera, J. F., Matthews, E. J., and Daniel, B. R. 2003. Predicting the carcinogenic potential of pharmaceuticals in rodents using molecular structural similarity and E-state indices. Regul. Toxicol. Pharmacol. 38(3):243-259.
25. Cremer, D. R., Rabeler, R., Roberts, A., and Lynch, B. 2006. Safety evaluation of ?-lipoic acid (ALA). Regul. Toxicol. Pharmacol. 46(1):29-41.
26. Crettaz, P., and Benigni, R. 2005. Prediction of the rodent carcinogenicity of 60 pesticides by the DEREKfW expert system. J. Chem. Inf. Model. 45(6):1864-1873.
27. Cross, K. P., Myatt, G., Yang, C., Fligner, M. A., Verducci, J. S., and Blower, P. E. 2003. Finding discriminating structural features by reassembling common building blocks. J. Med. Chem. 46(22):4770-4775.
28. Cruz-Monteagudo, M., Cordeiro, M. N., and Borges, F. 2007. Computational chemistry approach for the early detection of drug-induced idiosyncratic liver toxicity. J. Comput. Chem. Aug. 17.
29. Cui, M., Liu, Z., Qiu, Q., Li, H., and Li, L. 2005. Tumor induction in rats following exposure to short-term high dose aristolochi acid I. Mutagenesis 20(1):45-49.
30. De Vincenzi, M., Silano, M., Maialetti, F., and Scazzocchio, B. 2000. Constituents of aromatic plants: II Estragole. Fitoterapia 71:725-729.
31. Dietz, B., and Bolton, J. L. 2007. Botanical dietary supplements gone bad. Chem. Res. Toxicol. 20:586-590.
32. Dix, D. J., Houck, K. A., Martin, M. T., Richard, A. M., Setzer, R. W., and Kavlock, R. J. 2007. The ToxCast program for prioritizing toxicity testing of environmental chemicals. Toxicol. Sci. 95(1):5-12.
33. Drinkwater, N. R., Miller, E. C., Miller, J. A., Pitot, H. C. 1976. Hepatocarcinogenicity of estragole (1 Allyl 4 methoxybenzene) and 1 Hydroxyestragole in the mouse and mutagenicity of 1′ acetoxyestragole in bacteria. J. Nat. Inst. Cancer 57(6):1323-1331.
34. Ekins, S., Andreyev, S., Ryabov, A., Kirillov, E., Rakhmatulin, E. A., Bugrim, A., and Nikolskaya, T. 2005b. Computational prediction of human drug metabolism. Expert Opin. Drug Metab. Toxicol. 1(2):303-324.
35. Ekins, S., Nikolsky, Y., and Nikolskaya, T. 2005a. Techniques: application of systems biology to absorption, distribution, metabolism, excretion and toxicity. Trends Pharmacol. Sci. 26(4):202-209.
36. European Commission. 2007. "REACH (registration, evaluation, and authorization of chemicals)." http://ec.europa.eu/environment/chemicals/ reach/reach intro.htm.
37. European Parliament. 2003. Directive 2003/15/EC of the European Parliament and of the Council of 27 February 2003 amending Council Directive 76/768/EEC on the approximation of the laws of the Member States relating to cosmetic products. Official J. European Communities L66. March 11:26-35.
38. European Union's Scientific Committee on Food (EU-SCF). Opinion of the Scientific Committee on Food on estragole (1-alyl-4-methoxybenzene). scf/cs/flav/flavour/6 add2 final. 2001. Brussel, Belgium: European Commission Health & Consumer Protection Directorate-General.
39. Gold, L. S., and Aeiger, E. (Eds.). 1997. Handbook of Carcinogenic Potency and Genotoxicity Databases, CRC Press, Boca Raton, FL.
40. Gold, L. S., Manley, N. B., Slone, T. H., Rohrbach, L., and Garfinkel, G. B. 2005. Supplement to the Carcinogenic Potency Database (CPDB): Results of animal bioassays published in the general literature through 1997 and by the National Toxicology Program in 1997-1998. Toxicol. Sci. 85(2):747-808.
41. Gold, L. S., Slone, T. H., Ames, B. N., and Manley, N. B. 2001. Pesticide residues in food and cancer risk: a critical analysis. In: Krieger, R. (Ed.), Pesticide Residues in Food and Cancer Risk, Academic Press, San Diego, CA, pp. 799-843.
42. Gordon, W. P., Huitric, A. C., Seth, C. L., McClanahan, R. H., and Nelson, S. D. 1987. The metabolism of the abortifacient terpene, R-(+)-pulegone, to a proximate toxin methofuran. Drug. Met. Dispos. 15:589-594.
43. Gouni-Berthold, I., and Berthold, H. K. 2002. Policosanol: clinical pharmacology and therapeutic significance of a new lipid-lowering agent. Am. Heart J. 143:356-365.
44. Hagen, T. M., Liu, J., Lykkesfeldt, J., Wehr, C. M., Ingersoll, R. T., Vinarsky, V., Bartholomew, J. C., and Ames, B. N. 2002. Feeding acetyl-L-carnitine and lipoic acid to old rats significantly improves metabolic function while decreasing oxidative stress. Proc. Natl. Acad. Sci. USA. 19:1870-1875.
45. Hall, L. H., Kier, L. B., and Hall, M. L. 2006. Applications to drug discovery - ligand-based lead optimization in comprehensive medicinal chemistry II. In: Taylor, D. J., and Triggle, J. B. (Eds.), Topological QSAR Applications: Structure Information Representation in Drug Discovery, Elsevier, Oxford.
46. Hall, L. H., and Oser, B. L. 1965. Recent progress in the consideration of flavoring ingredients under the food additives amendment III GRAS substances. Food Technol. 19:253-271.
47. Hayes, J. D., and Pulford, D. J. 2001. The glutathione S-transferase super gene family: regulation of GST and the contribution of the isoenzymes to cancer chemoprotection and drug resistance. Crit. Rev. Biochem. Mol. Biol. 30:445-600.
48. Hirose, M., Mizoguchi, Y., Yaono, M., Tanaka, H., Yamaguchi, T., and Shirai, T. 1997. Effects of green tea catechins on the progression or late promotion stage of mammary gland carcinogenesis in female Sprague-Dawley rats pretreated with 7,12-dimethylbenz(a)anthracene. Cancer Lett. 31:151-159.
49. Hulzebos, E., Sijm, D., Traas, T., Posthumus, R., and Maslankiewicz, L. 2005. Validity and validation of expert (Q)SAR systems. SAR QSAR Environ. Res. 16(4):385-401.
50. Jacob, S., Henriksen, E. J., Tritschler, H. J., Augustin, H. J., and Dietze, G. J. 1996. Improvement of insulin-stimulated glucose-disposal in type 2 diabetes after repeated parenteral administration of thioctic acid. Exp. Clin. Endocrinol. Diabetes 104:284-288.
51. Jeurissen, S. 2007. Bioactivation and genotoxicity of the herbal constituents safrole, estragole and methyleugenol. Ph.D. Bioactivation and genotoxicity of the herbal constituents safrole, estragole and methyleugenol, Wageningen University.
52. Jeurissen, S. M. F., Punt, A., Boersma, M. G., Bogaards, J. J. P., Fiamegos, Y. C., Schilter, B., vanBladeren, P. J., Cnubben, N. H. P., and Rietjens, I. M. C. M. 2007. Human cytochrome P450 enzyme specificity for the bioactivation of estragole and related alkenylbenzenes. Chem. Res. Toxicol. 20(5): 798-806.
53. Kier, L. B., and Hall, L. H. 1999. Molecular Structure Description: The Electrotopological State, Academic Press, New York.
54. Klopman, G., Chakravarti, S. K., Harris, N., Ivanov, J., and Saiakhov, R. D. 2003. In-silico screening of high production volume chemicals for mutagenicity using the MCASE QSAR expert system. SAR QSAR Environ. Res. 14(2):165-180.
55. Kruhlak, N. L., Contrera, J. F., Benz, R. D., and Matthews, E. J. 2007. Progress in QSAR toxicity screening of pharmaceutical impurities and other FDA regulated products. Advanced Drug Delivery Rev. 59(1):43-55.
56. Lee, S. B., Cha, K. H., Selenge, D., Solongo, A., and Nho, C. W. 2007. The chemopreventive effect of taxifolin is exerted through ARE-dependent gene regulation. Biol. Pharm. Bull. 30:1074-1079.
57. Maliakal, P. P., Coville, P. F., and Wanwimolruk, S. 2001. Tea consumption modulates hepatic drug metabolizing enzymes in Wistar rats. J. Pharm. Pharmacol. 53:569-577.
58. Marshall, A., Graul, R. S., Morgan, M. Y., and Sherlock, S. 1982. Treatment of alcohol-related liver disease with thioctic acid: a six month randomized double-blind trial. Gut 23:1088-1093.
59. Matthews, E. J., and Contrera, J. F. 1998. A new highly specific method for predicting the carcinogenic potential of pharmaceuticals in rodents using enhanced MCASE QSAR-ES software. Regul. Toxicol. Pharmacol. 28(3):242-264.
60. Matthews, E. J., Kruhlak, N. L., Benz, R. D., and Contrera, J. F. 2004. Assessment of the health effects of chemicals in humans: I. QSAR estimation of the maximum recommended therapeutic dose (MRTD) and no effect level (NOEL) of organic chemicals based on clinical trial data. Curr. Drug. Discov. Technol. 1(1):61-76.
61. Mengs, U., Lang, W., and Poch, J. A. 1982. The carcinogenic action of aristolochi acids in rats. Arch. Toxicol. 51:107-119.
62. Mesa, A. R., Mas, R., Noa, M., Hernandez, C., Rodeiro, I., Gamez, R., Garcia, M., Capote, A., and Aleman, C. L. 1994. Toxicity of policosanol in beagle dogs: one-year study. Toxicol. Lett. 73:81-90.
63. Miller, J. A. 1994. Recent studies on the metabolic activation of chemical carcinogens. Cancer Res. 54(7 Suppl):1879S-1881S.
64. Miller, J. A., Miller, E. C., and Phillips, D. H. 1982. Themetabolic activation and arcinogenicity of alkenylbenzenes that occur naturally in many spices. In: Stich, H. F. (Ed.), Carcinogens and Mutagens in the Environment, CRC Press, Boca Raton, FL, pp. 83-96.
65. Moon, Y. J., Wang, X., and Morris, M. E. 2006. Dietary flavonoids: effects on xenobiotic and carcinogen metabolism. Toxicol. In Vitro 20:187-210.
66. Muller, L., Kasper, P., Muller-Tegethoff, K., and Pert, T. 1994. The genotoxic potential in vitro and in vivo of the allyl benzene etheric oils estragole, basil oil and trans-anethole. Mutat. Res. 325:129-136.
67. Mumtaz, M. M., Ruiz, P., and De Rosa, C. T. 2007. Toxicity assessment of unintentional exposure to multiple chemicals. Toxicol. Appl. Pharmacol. 223:104-113.
68. Nortier, J. L., Martinez, M. C., Schmeiser, H. H., Arlt, V. M., Bieler, C. A., Petein, M., Depierreux, M. F., De Pauw, L., Abramowicz, D., Vereerstraeten, P., and Vanherweghem, J. L. 2000. Urothelial carcinoma associated with the use of a Chinese herb (Aristolochia fangchi). N. Engl. J. Med. 342:1686-1692.
69. Nortier, J. L., Schmeiser, H. H., Muniz Martinez, M. C., Arlt, V. M., Vervaet, C., Garbar, C. H., Daelemans, P., and Vanherweghem, J. L. 2003. Invasive urothelial carcinoma after exposure to Chinese herbal medicine containing aristolochic acid may occur without severe renal failure. Nephrol. Dial. Transplant. 18(2):426-428.
70. Nortier, J. L., and Vanherweghem, J. L. 2002. Renal interstitial fibrosis and urothelial carcinoma associated with the use of a Chinese herb (Aristolochia fangchi). Toxicology 181-182:577-580.
71. Packer, L., and Wessel, K. 1997. Neuroprotection by the metabolic antioxidant alpha-lipoic acid. Free Radic. Biol. Med. 22:359-378.
72. Packer, L., Witt, E. H., and Tritschler, H. J. 1995. α-Lipoic acid as a biological antioxidant. Free Radic. Biol. Med. 19:227-250.
73. Patlewicz, G., Aptula, A. O., Uriarte, E., Roberts, D. W., Kern, P. S., Gerberick, G. F., Kimber, I., Dearman, R. J., Ryan, C. A., and Basketter, D. A. 2007. An evaluation of selected global (Q)SARs/expert systems for the prediction of skin sensitisation potential. SAR QSAR Environ. Res. 18(5):515-541.
74. Pearl, G. M., Livingston-Carr, S., and Durham, S. K. 2001. Integration of computational analysis as a sentinel tool in toxicological assessments. Curr. Top. Med. Chem. 1:247-255.
75. Phillips, D., Reddy, M. V., and Randerath, K. 1984. 32P-Postlabelling analysis of DNA adducts formed in the livers of animals treated with safrole, estragole, and other naturally occurring alkenylbenzenes. II. Newborn male B6C3F1 mice. Carcinogenesis 5(12):1623-1628.
76. Pollard, A., Chibnall, A. C., and Piper, S. H. 1933. The isolation of n-octacosanol from wheat wax. Biochem J 27:1889-1893.
77. Randerath, K. H. R. E., Phillips, D. H., and Reddy, M. V. 1984. 32P-Postlabelling analysis of DNA adducts formed in the livers of animals treated with safrole, estragole and other naturally occurring alkenylbenzenes. I. Adult female CD-1mice. Carcinogenesis 5:1613-1622.
78. Reed, L. J., DeBusk, B. G., Gansalus, I. C., and Jr., Hornberger, C. S. 1951. Crystalline α-lipoic acid: a catalytic agent associated with pyruvate dehydrogenase. Science 114:93-94.
79. Rietjens, I. M. C., Martena, M., Boersma, M., Spiegelenberg, W., and Alink, G. M. 2005. Molecular mechanisms of toxicity of important food-borne phytotoxins. Mol. Nutr. Food Res. 49:131-158.
80. Richard, A. M. 1998. Structure-based methods for predicting mutagenicity and carcinogenicity: are we there yet?. Mutat. Res. 400(1-2):493-507.
81. Roberts, G., Myatt, G. J., Johnson, W. P., Cross, K. P., and Blower Jr, P. E. 2000. LeadScope: software for exploring large sets of screening data. J. Chem. Inf. Comput. Sci. 40:1302-1314.
82. Robisch, G., Schimmer, O., and Goggelmann, W. 1982. Aristolochic acid is a direct mutagen in Salmonela typhimurium. Mutat. Res. 105:201.
83. Rodriguez, M., and Garcia, H. 1998. Evaluation of peri- and post-natal toxicity of policosanol in rats. Teratog. Carcinog. Mutagen. 18:1-7.
84. Rosenkranz, H. S. 2003. SAR in the assessment of carcinogenesis: the MultiCASE approach. In: Benigni, R. (Ed.), Quantitative Structure-Activity Relationship (QSAR) Models of Mutagens and Carcinogens, CRC Press, Boca Raton, FL, pp. 175-206.
85. Saller, R., Meier, R., and Brignoli, R. 2001. The use of silymarin in the treatment of liver diseases. Drugs 61:2035-2063.
86. Schumann, J., Prockl, J., Kiemer, A. K., Vollmar, A. M., Bang, R., and Tiegs, G. 2003. Silibinin protects mice from T cell-dependent liver injury. J. Hepatol. 39:333-340.
87. Seaton, T. A., Jenner, P., and Marsden, C. D. 1996. Thioctic acid does not restore glutathione levels or protect against the potentiation of 6-hydroxydopamine toxicity induced by glutathione depletion in rat brain. J. Neural Transm. 103:315-329.
88. Singh, A. K. 2001. Development of QSAR models to predict estrogenic, carcinogenic, and cancer protective effets of phytoestrogens. Cancer Invest. 19(2):201-216.
89. Singh, D. K., Li, L., and Porter, T. D. 2006. Policosanol inhibits cholesterol synthesis in hepatoma cells by activation of AMP-kinase. J. Pharmacol. Exp. Ther. 318:1020-1026.
90. Smith, R. L., Adams, T. B., Doull, J., Feron, V. J., Goodman, J. L., Marnett, L. J., Portoghese, P. S., Waddel, W. J., Wagner, B. M., Rogers, A. E., Caldwell, J., and Sipes, I. G. 2002. Safety assessment of allylalkoxybenzene derivatives used as flavouring substances - methyl eugenol and estragole. Food Chem. Toxicol. 40:851-870.
91. Stilborova, M., Frie, E., Sopko, B., Wiessler, M., and Schmeiser, H. 2002. Carcinogenic aristolochic acids upon activation by DT-diaphorase form adducts found in DNA of patients with Chinese herbs nephropathy. Carcinogenesis 23:617-625.
92. Swanson, A. B., Miller, E. C., and Miller, J. A. 1981. The side-chain epoxidation and hydroxylation of the hepatocarcinogens safrole and estragole and some related compounds by rat and mouse liver microsomes. Biochim. Biophy. Acta 673(4):504-516.
93. Talalay, P., De Long, M. J., and Prochaska, H. J. 1988. Identification of a common chemical signal regulating the induction of enzymes that protect against chemical carcinogenesis. Proc. Natl. Acad. Sci. USA 85:8261-8265.
94. Tanigawa, S., Fujii, M., and Hou, D. X. 2007. Action of Nrf2 and Keap1 in ARE-mediated NQO1 expression by quercetin. Free Radic. Biol. Med. 42:1690-1703.
95. Theodoratou, E., Kyle, J., Cetnarskyj, R., Farrington, S. M., Tenesa, A., Barnetson, R., Porteous, M., Dunlop, M., and Campbell, H. 2007. Dietary flavonoids and the risk of colorectal cancer. Cancer Epidemiol. Biomarkers Prev. 16:684-693.
96. Tsubono, Y., Nishino, Y., Komatsu, S., and Hsieh, C.-C. 2001. Green tea and the risk of gastric cancer in Japan. N. Engl. J. Med. 344:632-636.
97. Valerio, L. G., Jr., Arvidson, K. B., Chanderbhan, R. F., and Contrera, J. F. 2007. Prediction of rodent carcinogenic potential of naturally occurring chemicals in the human diet using high-throughput QSAR predictive modeling. Toxicol. Appl. Pharmacol. 222:1-16.
98. Valerio, L. G., Jr., Kepa, J. K., Pickwell, G. V., Quattrochi, L. C. 2001. Induction of human NAD(P)H:quinone reductase (NQO1) gene expression by the flavonol quercetin. Toxicol. Lett. 119:49-57.
99. Vanhaelen, M., Vanhaelen-Fastre, R., But, P., and Vanherweghem, J.-L. 1994. Identification of aristolochic acid in Chinese herbs. Lancet 343:174.
100. Vanherweghem, L., Depierreux, M., Tielemans, C., and Abramowicz, D. 1993. Rapidly progressive interstitial renal fibrosis in young women: association with slimming regimen including Chinese herbs. Lancet 341:387-391.
101. Varghese, L., Agarwal, C., Tyagi, A., Singh, R. P., and Agarwa, R. 2005. Silibinin efficacy against human hepatocellular carcinoma. Clin. Cancer Res. 11:8441-8448.
102. Vaya, J., and Tamir, S. 2004. The relation between the chemical structure of flavonoids and their estrogen-like activities. Curr Med Chem. 11:1333-1343.
103. Venkatapathy, R., Moudgal, C. J., and Bruce, R. M. 2004. Assessment of the oral rat chronic lowest observed adverse effect level model in TOPKAT, a QSAR software package for toxicity prediction. J. Chem. Inf. Model. 44(5):1623-1629.
104. Vogel, G., Tuchweber, B., Trost, W., and Mengs, U. 1984. Protection by silibinin against Amanita phalloides intoxication in beagles. Toxicol. Appl. Pharmacol. 73:355-362.
105. Wada, H., Shintani, D., and Ohlrogge, J. 1997. Why do mitochondria synthesize fatty acids? Evidence for the involvement of lipoic acid production. Proc. Nati. Acad. Sci. 94:1591-1596.
106. Wakazono, H., Gardlner, I., Eliasson, E., Coughtrie, M. W. H., Kenna, J. G., and Caldwell, J. 1998. Immunochemical identification of hepatic protein adducts derived from estragole. Chem. Res. Toxicol. 11(8):863-872.
107. Wang, Y., Wang, X., and Cheng, Y. 2006. A computational approach to botanical drug design by modeling quantitative composition-activity relationship. Chem. Biol. Drug Design 68(3):166-172.
108. Weisburger, J. H., Rivenson, A., Reinhardt, J., Kelloff, G. J., Boone, C. W., Steele, V. E., Balintine, D. A., Pittman, B., and Zang, E. 1998. Effect of tea extracts, polyphenols, and epigallocatechin gallate on azoxymethane-induced colon cancer. Exp. Biol. Med. 217:104-108.
109. Williams, S. N., Pickwell, G. V., and Quattrochi, L. C. 2003. A combination of tea (Camellia senensis) catechins is required for optimal inhibition of induced CYP1A expression by green tea extract. J. Agric. Food Chem. 51:6627-6634.
110. Woo, Y. T., and Lai, D. Y. 2005. OncoLogic: a mechanism-based expert system for predicting the carcinogenic potential of chemicals. In: Helma, C. (Ed.), Predictive Toxicology, Dekker, New York.
111. Woo, Y. T., Lai, D. Y., Argus, M. F., and Arcos, J. C. 1995. Development of structure-activity relationship rules for predicting carcinogenic potential of chemicals. Toxicol. Lett. 79(1-3):219-228.
112. Wright, A. D., deNys, R., Angerhofer, C. K., Pezzuto, J. M., and Gurrath, M. 2006. Biological activities and 3D QSAR studies of a series of Delisea pulchra (cf. fimbriata) derived natural products. J. Nat. Prod. 69(8):1180-1187.
113. Xue, C. X., Zhang, X. Y., Liu, M. C., Hu, Z. D., and Fan, B. T. 2005. Study of probabilistic neural networks to classify the active compounds in medicinal plants. J. Pharm. Biomed. Anal. 38(3):497-507.
114. Yang, C. S., Maliakal, P., and Meng, X. 2002. Inhibition of carcinogenesis by tea. Annu. Rev. Pharmacol. Toxicol. 42:25-54.
115. Zhou, S., Koh, H.-L., Gao, Y., Gong, Z-.Y., and Lee, E. J. D. 2004. Herbal bioactivation: the good, the bad and the ugly. Life Sci. 74:935-968.