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D. J. Rhee, Y. H. Ooi, D.-J. Oh; Effects of Topiramate on Ciliary Body Smooth Muscle Cells. Invest. Ophthalmol. Vis. Sci. 2007;48(13):5900.
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Topiramate (Topamax) has been associated with ocular side effects ranging from acute myopia and bilateral acute angle-closure glaucoma. These side effects are rare and are believed to be idiosyncratic reactions to the sulfamate moiety. Our purpose was to see which gene(s) or enzyme systems are affected in ciliary body smooth muscle (CBSM) cells.
Cultures of CBSM cells from 4 separate donors aged, 43, 45, 65, and 79 years were used. Passage-4 CBSM cells were grown to confluence and incubated in serum free media for two days. Cultures were incubated with 3 mg/mL (peak serum concentration), 30 mg/mL of topiramate or vehicle control for 24 hours. 10 µg of total RNA at concentration of 0.5 µg/µL isolated from treated cultures was used for the microarray analysis. A genome-wide human 65-mer oligonucleotide expression chip containing 18,670 uniset genes whose library was obtained from Compugen/Sigma was used. The median normalized data from control and experimental samples are compared to each other in fold change.
The expression of sperm associated antigen 7 and cytochrome P450 4B1 were elevated above 3-fold at 3 mg/mL while ADP-ribosylation-like factor 6 interacting protein 2, placenta-specific 1, carbosypeptidase E, keratin 18, and spermidine synthase were elevated between 2 and 3-fold at 3 mg/mL. At 10x the peak serum concentration, sperm associated antigen 7, KIAA0326 protein, ELAV-like 4, recombination activating gene 1, and chemokine ligand 27 were elevated between 2- and 3-fold.
Based on the typically rare and idiosyncratic frequency of bilateral acute angle-closure glaucoma (AACG) as well as the usually rare distribution of functionally significant polymorphisms in cytochrome P450 enzymes, our results implicate cytochrome P450 4B1 in the pathogenesis of topiramate induced AACG.
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