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eBook details
- Title: CYP2C9*2 and CYP2C9*3 Alleles Confer a Lower Risk for Myocardial Infarction (Technical Briefs)
- Author : Clinical Chemistry
- Release Date : January 01, 2004
- Genre: Chemistry,Books,Science & Nature,
- Pages : * pages
- Size : 180 KB
Description
Cytochrome P-450 (CYP) genes encode for membrane-bound, heme-containing enzymes that catalyze the oxidation of various drugs and endogenous substrates such as vitamin D, steroids, or fatty acids, including arachidonic acid (AA). CYP enzymes of the P-450 2C9 subfamily are produced in the liver, are responsible for 50% of the epoxygenase activity in human liver, and metabolize a wide variety of clinically important drugs, including losartan, torsemide, and S-warfarin (1). Furthermore, CYP2C9 may also play a role in the regulation of vascular tone. In addition to nitric oxide (NO) and prostacyclin, endothelial cells synthesize and release endothelium-derived hyperpolarizing factor (EDHF), which causes hyperpolarization of underlying vascular smooth muscle cells via activation of [Ca.sup.2+]-activated [K.sup.+] channels (2). EDHF has been described as an important regulator of vascular tone under certain pathologic conditions and in certain vascular beds, such as the coronary microcirculation (3). Interestingly, EDHF production seems to be inhibited by NO and/or prostacyclin. There is now compelling evidence that the hyperpolarizing factor produced by coronary arteries is a CYP epoxygenase-derived metabolite of AA. Recently, it has been shown that decreased concentrations of CYP2C attenuate EDHF-mediated vascular response in porcine coronary artery endothelial cells (4). This effect appears to be directly attributable to the regulation of an enzyme homologous to CYP2C9 and the generation of the CYP metabolite 11,12-epoxyeicosatrienoic acid (5). Changes in the amino acid sequence of CYP2C9 can affect both the activity and substrate specificity of CYP2C9. Previously, three alleles were identified in the Caucasian population: CYP2C9*1, CYP2C9*2, and CYP2C9*3. The CYP2C9*1 allele encodes the wild-type protein, and the CYP2C9*2 allele contains a C-to-T transition, leading to substitution of cysteine by arginine at amino acid position 144. The CYP2C9*3 allele is defined by an A-to-C nucleotide substitution that leads to an exchange of leucine by isoleucine at amino acid position 359. Both variant alleles are associated with significantly reduced enzyme activity (6,7). We hypothesized that reduced CYP2C9 activity attributable to genetic alterations may modulate vascular function and influence the risk of vascular disease.
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