Molecular classification of doxazosin-induced alterations in the rat prostate using gene expression profiling.
We investigated molecular changes that occurred during chronic administration of doxazosin, an alpha1-adrenoceptor (AR) antagonist, using Affymetrix GeneChip analysis of gene expression. Rats were treated with doxazosin (4 mg/kg/day subcutaneously, supplemented with 4 mg/kg/day orally) for 12 weeks. Labeled cRNA was prepared and the subsequent hybridization to rat 230A arrays was performed. The alterations in gene expression levels of candidate genes identified by microarray analysis with potential biological relevance were verified by real-time reverse transcription polymerase chain reaction (RT-PCR) using SYBR Green I. Doxazosin treated rats had significantly heavier prostates compared to control rats. Microarray analysis revealed that chronic doxazosin treatment caused changes in the expression levels of 625 genes, of which 39 were related to cell death, necrosis, growth, proliferation and G-protein signalling pathways in the rat prostate. Furthermore, RT-PCR experiments, in accord with the microarray analysis, indicated that chronic doxazosin treatment caused an up-regulation in the mRNA expression level of clusterin, an antiapoptotic mediator, and epiregulin, a mitogen, in the ventral and dorsolateral prostate, respectively. These findings, that demonstrate chronic doxazosin administration causes significant changes in the expression of several hundred genes in the rat prostate, may provide insight into the long-term efficacy of alpha1-AR antagonists in the treatment of benign prostatic hyperplasia.
Yono
Makoto
M
Section of Urology, Yale University School of Medicine, P.O. Box 208041, New Haven, CT 06520, USA.
Foster
Harris E
HE
Shin
David
D
Mane
Shrikant
S
Latifpour
Jamshid
J
D000284:Administration, Oral; D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D016000:Cluster Analysis; D017292:Doxazosin / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects*; D020869:Gene Expression Profiling; D007279:Injections, Subcutaneous; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D009929:Organ Size / Q000187:drug effects; D011467:Prostate / Q000187:drug effects* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction
D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D012333:RNA, Messenger; D017292:Doxazosin