[Pharmacogenomics and pharmainformatics].
Pharmacogenomics is defined to identify the genes which are involved in determining the responsiveness and to distinguish responders and non-responders to a given drug. Genome sequencing, transcriptome and proteome analysis are of particular significance in pharmacogenomics. Sequencing is used to locate polymorphisms, and monitoring of gene expression can provide clue about the genomic response to disease and treatment. The transcriptome analysis can be done by methods of random cDNA sequencing (expressed sequence tag project, body map project, serial analysis of gene expression, et al), mRNA display (differential display, fluorescent differential display, RNA arbitraly primed PCR, molecular indexing, gene expression fingerprinting, et al) and differential hybridization(cDNA high density filter, cDNA microarray, oligomicrochip, et al). We used transcriptome analysis to identify therapeutic target genes by studying change of gene expression in animal models of cerebral vasospasm (1) and of hypoxia/ischemia and found novel drug target candidates through this pharmacogenomic strategy (2). We found remarkable up-regulation of heme oxygenase-1(HO-1) mRNA in the basilar artery and it might be closely related to the occurrence of delayed vasospasm after subarachnoid hemorrhage. In this report, we clearly demonstrate that intrathecal administration of antisense HO-1 oligodeoxynucleotide aggravates vasospasm, suggesting HO-1 gene induction has spasmolytic effects. Furthermore, we found the protective effects of HO-1 gene induction by endogenous or clinical compounds in cerebral vasospasm. Therapeutic gene induction of HO-1 could be a novel strategy for the prevention and treatment of Hb-induced pathologic conditions including delayed cerebral vasospasm. Our results suggest that the pharmacogenomic transcriptome analysis and pharmainformatics has the potential for strategy to define novel drug targets in various diseases (3). (1) J Clin Invest 104: 59-66, 1999. (2) J Biol Chem 276: 19921-19928, 2001. (3) J Cardiovasc Pharm 36: S1-S4, 2000.
Tanaka
Toshio
T
Department of Molecular and Cellular Pharmacology, Mie University School of Medicine.
Nishimura
Yuhei
Y
Tsunoda
Hiroshi
H
Kitaoka
Yoshikuni
Y
Naka
Michiko
M
D000818:Animals; D030541:Databases, Genetic; D015195:Drug Design; D015316:Genetic Therapy; D015894:Genome, Human; D006801:Humans; D005810:Multigene Family; D010597:Pharmacogenetics; D020543:Proteome; D014158:Transcription, Genetic
D020543:Proteome