Mechanism for covalent binding of rofecoxib to elastin of rat aorta.
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Oitate M, Hirota T, Takahashi M, Murai T, Miura S, Senoo A, Hosokawa T, Oonishi T, Ikeda T
Mechanism for covalent binding of rofecoxib to elastin of rat aorta.
J Pharmacol Exp Ther. 2007 Mar;320(3):1195-203. Epub 2006 Dec 12.
- PubMed ID
- 17164475 [ View in PubMed]
- Abstract
We have previously reported that oral administration of [(14)C]rofecoxib to rats resulted in the long retention of radioactivity by the aorta as a consequence of covalent binding to elastin. Treatment of rats with alpha-phenyl-alpha-propylbenzeneacetic acid 2-[diethylamino]-ethyl ester hydrochloride (SKF-525A), a cytochrome P450 inhibitor, significantly decreased the systemic exposure of 5-hydroxyrofecoxib, one of the main metabolites of rofecoxib, whereas there was no statistically significant change in the retention of radioactivity from [(14)C]rofecoxib in the aorta. On the other hand, the aortic retention of radioactivity closely correlated to the systemic exposure of unchanged rofecoxib in the dose range between 2 and 10 mg/kg. A covalent binding study of [(14)C]rofecoxib in vitro using rat aorta homogenate in the presence of d-penicillamine, hydralazine, beta-aminopropionitrile, and sodium borohydride suggested that the aldehyde group of allysine in elastin was relevant to the covalent binding. In a model reaction using benzaldehyde, rofecoxib but not 5-hydroxyrofecoxib reacted with the aldehyde group of benzaldehyde in a manner of condensation reaction under a physiological pH condition. A histopathological examination using an electron microscope demonstrated that multiple oral administration of rofecoxib to rats caused marked degradation of the elastic fiber system of the aorta. These results suggested that rofecoxib as such is reactive in vivo, undergoing a condensation reaction with allysine, thereby preventing the formation of cross-linkages in elastin, i.e., desmosine and isodesmosine, and causing the degradation of the elastic fibers.