The ile359-to-leu (I359L) substitution results from a 1075A-C transversion in the CYP2C9 gene and is also known as rs1057910 and CYP2C9*3. The variant leads to reduced warfarin metabolism and increased risk of bleeding (Ross et al., 2010).
Extensive interindividual variation in the response to a given dose Sullivan-Klose et al. (1996) demonstrated that the form of CYP2C9 in which ile359 is replaced by leucine is the basis of poor metabolizing of tolbutamide, the sulfonylurea hypoglycemic agent used in the treatment of diabetes mellitus (NIDDM; 125853). The frequency of the leu359 allele was found to be 0.06 in the Caucasian-American population and 0.005 in African Americans. The frequency of the leu359 allele was 0.026 in Chinese-Taiwanese. They found that the leu359 allelic variant of CYP2C9 also has a lower affinity and a lower intrinsic clearance for S-warfarin 7-hydroxylation than the ile359 variant. Presumably, 7-hydroxylation has an important role in terminating the anticoagulant activity of warfarin in vitro, and individuals who are homozygous for the leu359 variant might require lower doses of this anticoagulant.
In a patient who was unusually sensitive to warfarin therapy (see 122700), Steward et al. (1997) identified homozygosity for I359L, the so-called CYP2C9*3 allele. The patient, who was taking 0.5 mg of warfarin daily, had an S-to-R enantiomer ratio of 3.9:1, whereas control patients taking 4 to 8 mg of warfarin daily had S-to-R ratios of about 0.5:1. Steward et al. (1997) concluded that expression of CYP2C9*3 is associated with diminished clearance of the more potent S-warfarin, and that analysis of the plasma S-to-R warfarin ratio might serve as a useful alternative test to genotyping.
Kidd et al. (1999) described a 29-year-old male Caucasian who had participated in 6 bioequivalence studies over a period of several years. The patient displayed severe hypoglycemia after a single dose of glipizide, a second generation sulfonylurea structurally similar to tolbutamide and used as an oral hypoglycemic agent. His oral clearance of phenytoin was 21% of the mean of 11 other individuals, and his oral clearance of glipizide was only 18% of the mean of 10 other individuals. His oral clearance of nifedipine (a CYP3A4 (124010) substrate) and chlorpheniramine (a CYP2D6 (see 124030) substrate) did not differ from that of other individuals studied. Genotype testing demonstrated that the individual was homozygous for the leu359 allele and did not possess any of the known defective CYP2C19 (124020) alleles. These studies established that the leu359 allele is responsible for the phenytoin and glipizide/tolbutamide poor metabolizer phenotype.
In a study of 281 epileptic patients treated with phenytoin, Tate et al. (2005) found a significant association between the maximum dose needed and the CYP2C9*3 allele (I359L). Mean phenytoin doses for individuals with 0, 1, or 2 copies of the *3 allele were 354, 309, and 250 mg, respectively, indicating a trend of reduction in maximum dose needed to control symptoms.
Ross et al. (2010) genotyped 963 individuals from 7 geographic regions for the CYP2C9*3 variant. The highest frequencies were observed in Europe (4 to 21%), the Middle East (3 to 11%) and Central/South Asia (5 to 15%). The allele was not observed in Africa or most populations from the Americas, except the Pima (7%). In Oceania, the allele was not present in Melanesians, but in Papua New Guinea the frequency was 12%. The allele was absent in many populations in East Asia, but reached frequencies of 10% or higher in some populations, such as the Tu, Tujia and Xibo. Similar frequencies were found in a Canadian cohort of 316 individuals of European, East Asian, and South Asian ancestry.
