tailieunhanh - PREDICTIVE TOXICOLOGY - CHAPTER 3

Độc tính không lường trước được là một trong những lý do chính cho sự thất bại của ứng cử viên thuốc. Một kiểm tra đáng tin cậy của ứng cử viên ma túy trên các tác dụng phụ độc hại trong giai đoạn đầu của sự phát triển thành phần dẫn có thể giúp đỡ trong việc ưu tiên ứng cử viên và tránh việc sử dụng vô ích của các thử nghiệm lâm sàng và xét nghiệm động vật đắt tiền. Một sự hiểu biết tốt hơn về nguyên nhân cơ bản của phản ứng độc tính và. | 3 Computational Biology and Toxicogenomics KATHLEEN MARCHAL FRANK DE SMET KRISTOF ENGELEN and BART DE MOoR ESAT-SCD . Leuven Leuven Belgium 1. INTRODUCTION Unforeseen toxicity is one of the main reasons for the failure of drug candidates. A reliable screening of drug candidates on toxicological side effects in early stages of the lead component development can help in prioritizing candidates and avoiding the futile use of expensive clinical trials and animal tests. A better understanding of the underlying cause of toxicological and pharmacokinetic responses will be useful to develop such screening procedure 1 . Pioneering studies such as Refs. 2-5 have demonstrated that observable classical toxicological endpoints are 37 2005 by Taylor Francis Group LLC 38 Marchal et al. reflected in systematic changes in expression level. The observed endpoint of a toxicological response can be expected to result from an underlying cellular adaptation at molecular biological level. Until a few years ago studying gene regulation during toxicological processes was limited to the detailed study of a small number of genes. Recently high-throughput profiling techniques allow us to measure expression at mRNA or protein level of thousands of genes simultaneously in an organism tissue challenged with a toxicological compound 6 . Such global measurements facilitate the observation not only of the effect of a drug on intended targets on-target but also of side effects on untoward targets off-target 7 . Toxicogenomics is the novel discipline that studies such large scale measurement of gene protein expression changes that result from the exposure to xenobiotics or that are associated with the subsequent development of adverse health effects 8 9 . Although toxicogenomics covers a larger field in this chapter we will restrict ourselves to the use of DNA arrays for mechanistic and predictive toxicology 10 . . Mechanistic Toxicology The main objective of mechanistic toxicology is to obtain