An additional defective allele, CYP2C19*5, contributes to the S-mephenytoin poor metabolizer phenotype in Caucasians

Ibeanu, Gordon C.; Blaisdell, Joyce; Ghanayem, Burhan I.; Beyeler, Christine; Benhamou, Simone; Wilkinson, Grant R.; Dayer, P.; Daly, Ann K.; Goldstein, Joyce A.

doi:10.1097/00008571-199804000-00006

Cited by 91 publications

(67 citation statements)

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“…Figure 3 shows a compilation of reported naturally occurring P450 variants. Among these, the R433W variant of CYP2C19 (*5 allele) (Ibeanu et al, 1998) and the R448H variant of CYP11B1 (Curnow et al, 1993) had completely abolished S-mephenytoin and cortisol 11␤-hydroxylase activities in vivo, respectively. For the mutation to W in CYP2C19, a loss of activity is predicted because W is not included in the PROSITE pattern at this position (RKHPT).…”

Section: Resultsmentioning

confidence: 99%

A Natural Variant of the Heme-Binding Signature (R441C) Resulting in Complete Loss of Function of CYP2D6

Klein

Tatzel²,

Raimundo³

et al. 2007

Drug Metab Dispos

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ABSTRACT:A new variant allele CYP2D6*62 (g.4044C>T; R441C) of the drugmetabolizing cytochrome P450 (P450) CYP2D6 was identified in a person with reduced sparteine oxidation phenotype, which was unexpected based on a genetic CYP2D6*1A/*41 background. The recombinantly expressed variant protein had no activity toward propafenone as a result of missing heme incorporation. Sequence alignment revealed that the positively charged R441 residue is part of the heme-binding signature but not strictly conserved among all the P450s. A compilation of described P450 monooxygenase variants revealed that other enzymes can functionally tolerate even nonconservative amino acid changes at the corresponding position (i.e., the invariant cysteine 2). This suggests that heme binding in mammalian P450s depends not only on the integrity of the heme-binding signature but also on other family-and subfamily-specific sequence determinants.

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Section: Resultsmentioning

confidence: 99%

A Natural Variant of the Heme-Binding Signature (R441C) Resulting in Complete Loss of Function of CYP2D6

Klein

Tatzel²,

Raimundo³

et al. 2007

Drug Metab Dispos

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“…[58][59][60] Similarly, 10 SNPs were found on the gene coding cytochrome P450 2C19, but only 9 alleles were defined. 61,62) As for the MDR1 gene, polymorphism at position 3435 was significantly linked with polymorphism at position 2677 in healthy Japanese subjects (Table 4). 63) As shown in Table 4, 31.7% of the subjects with C/C 3435 were homozygotic for the G-allele at position 2677 (G/G 2677 ), and 71.4% with T/T 3435 were homozygotic for the T-allele at position 2677 (T/T 2677 ).…”

Section: Mdr1mentioning

confidence: 96%

MDR1 Genotype-Related Pharmacokinetics and Pharmacodynamics.

Sakaeda

Nakamura

Okumura

2002

Biological & Pharmaceutical Bulletin

169

110

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The multidrug resistant transporter MDR1/P-glycoprotein, the gene product of MDR1, is a glycosylated membrane protein of 170 kDa, belonging to the ATP-binding cassette superfamily of membrane transporters. MDR1 acts as an energy-dependent efflux pump that exports its substrates out of cells. MDR1 was originally isolated from resistant tumor cells as part of the mechanism of multidrug resistance, but over the last decade, it has been elucidated that human MDR1 is also expressed throughout the body to confer intrinsic resistance to the tissues by exporting unnecessary or toxic exogeneous substances or metabolites. A number of structurally unrelated drugs are substrates for MDR1, and MDR1 and other transporters are recognized as an important class of proteins for regulating pharmacokinetics and pharmacodynamics. In 2000, Hoffmeyer et al. performed a systemic screening for MDR1 polymorphisms and detected 15 single nucleotide polymorphisms (SNPs). They also indicated that a polymorphism in exon 26 at position 3435 (C3435T), a silent mutation, affected the expression level of MDR1 protein in duodenum, and thereby the intestinal absorption of digoxin. To date, the genotype frequencies of C3435T have been investigated extensively using a larger population and interethnic difference has been elucidated, and a total of 28 SNPs have been found at 27 positions on the MDR1 gene. Clinical studies on MDR1 genotype-related MDR1 expression and pharmacokinetics have also been performed around the world; however, results were not always consistent with Hoffmeyer's report. In this review, published reports are summarized for the future individualization of pharmacotherapy based on MDR1 genotyping. In addition, recent investigations have raised the possibility that MDR1 and related transporters play a fundamental role in regulating apoptosis and immunology, and in fact, there are reports of MDR1-related susceptibility to inflammatory bowel disease, HIV infection and renal cell carcinoma. Herein, these issues are also summarized, and the current status of the knowledge in the area of pharmacogenomics of other transporters is briefly introduced.

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“…All PCR primers are indicated from 5' to 3' end and are provided in Table 1. The primers sequences were based on published literature [14][15][16][17].…”

Section: Cyp2c19 Genotypingmentioning

confidence: 99%