A Single Nucleotide Polymorphism of CYP2B6 Found in Japanese Enhances Catalytic Activity by Autoactivation

Ariyoshi, Noritaka; Miyazaki, Masafumi; Toide, Kenji; Sawamura, Yu ichi; Kamataki, Tetsuya

doi:10.1006/bbrc.2001.4524

Cited by 121 publications

(83 citation statements)

References 17 publications

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“…Comparing the 95% confidence intervals, this is in the same range as reported in a Japanese (19.9%, n ¼ 88) 23 and a German (28.6%, n ¼ 215) population. 24 In addition, for *6 carriers we observed a tendency of decreased CYP2B6 protein level (Figure 1), and a tendency of a relatively higher proportion of having nondetectable protein (Table 2).…”

Section: Discussionsupporting

confidence: 84%

“…Default PCR conditions for Taqman (501C Â 2 min, 951C Â 10 min, (951C Â 15 s, 601C Â 1 min) Â 35 cycles) was used. Primers (CyberGene AB, Novum Research Park, Stockholm, Sweden) used for the analysis of CYP2B6*6 were as described by Ariyoshi et al 23 The Polymerase chain reaction (PCR) was performed in a total volume of 25 ml, including 50 ng genomic DNA, 1 Â PCR buffer II (Perkin-Elmer, Foster City, CA, USA), 1.5 mM MgCl 2 , 0.2 mM dNTP mix, 500 nM of each primer, and 0.2 U of AmpliTaq DNA polymerase (Perkin-Elmer, Foster City, Ca, USA). After 3 min of denaturation at 941C, the samples were subjected to the following amplification programme: denaturation at 951C for 30 s, annealing at 581C for 30 s, extension at 721C for 45 s for 35 cycles with a prolonged last step at 721C for 7 min.…”

Section: Genotyping Of Cyp2b6mentioning

confidence: 99%

“…4,9,20 Part of the variation was considered to be caused by regulatory phenomena at the transcriptional or translational level. 5,21,22 Subsequently, genetic polymorphism of this enzyme was discovered 23,24 and this contributes to the variation. An amino-acid substitution, Gln 172 His, caused by the G516T (CYP2B6*6) SNP was described to enhance 7-ethoxycoumarin O-deethylase activity.…”

Section: Introductionmentioning

confidence: 99%

“…An amino-acid substitution, Gln 172 His, caused by the G516T (CYP2B6*6) SNP was described to enhance 7-ethoxycoumarin O-deethylase activity. 23 A total of nine novel point mutations have now been identified, of which five result in amino-acid substitutions in exons 1,4,5, and 9, and the rest are silent mutations. 24 Carriers of the C1459T variant (CYP2B6*5) were found to have significantly lower S-mephenytoin N-demethylase activity.…”

Section: Introductionmentioning

confidence: 99%

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Role of polymorphic human CYP2B6 in cyclophosphamide bioactivation

et al. 2003

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The role of polymorphic CYP2B6 in cyclophosphamide (CPA) bioactivation was investigated in human liver microsomes. A total of 67 human liver specimens were first genotyped with respect to the CYP2B6*5 and CYP2B6*6 variant alleles. CYP2B6 apoprotein levels in 55 liver microsomal preparations were assessed by immunoblotting. 4-Hydroxy-CPA and hydroxy-bupropion were quantified by using HPLC and LC-MS, respectively. 7-Ethoxy-4-trifluoromethyl coumarin O-deethylase activity was measured fluorometrically. The frequencies of CYP2B6*5 and CYP2B6*6 mutant alleles were 9.0 and 16.4%, respectively. CYP2B6 protein expression was detected in 80% of the samples, with a large variation (0.003-2.234, arbitrary units). There was a high correlation between CYP2B6 apoprotein content and CPA 4-hydroxylation (n ¼ 55, r ¼ 0.81, Po0.0001). When based on the CYP2B6 apoprotein levels, the *6 carriers had significantly higher CPA 4-hydroxylation (Po0.05). CPA 4-hydroxylation also correlated significantly with other CYP2B6-specific reactions (n ¼ 20, Po0.0001). V max and K m for CPA 4-hydroxylation in recombinant CYP2B6 enzyme were 338 nmol/min/nmol enzyme and 1.4 mM, respectively. CYP2B6 showed much higher in vitro intrinsic clearance than previously observed in recombinant CYP2C19 and CYP2C9 variants in yeast expression system. Our results demonstrate that the polymorphic CYP2B6 is a major enzyme in the bioactivation of CPA. Moreover, we identified a strong impact of CYP2B6*6 on CPA 4-hydroxylation.

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Section: Discussionsupporting

confidence: 84%

Section: Genotyping Of Cyp2b6mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Role of polymorphic human CYP2B6 in cyclophosphamide bioactivation

et al. 2003

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“…In recent years extensive studies have shown that several mammalian cytochromes P450 (1A2, 2C9, 2B6, and 3A4) exhibit homo-and heterotropic cooperativity toward a number of substrates [1][2][3][4][5][6][7]. The most prominent examples of these phenomena are observed with P450 3A4 (CYP3A4), and studies of cooperativity of this enzyme are of considerable importance in elucidating the mechanisms of drug metabolism and drug-drug interactions in humans [7].…”

Section: Introductionmentioning

confidence: 99%

Role of subunit interactions in P450 oligomers in the loss of homotropic cooperativity in the cytochrome P450 3A4 mutant L211F/D214E/F304W

Fernando

Davydov

Chin

et al. 2007

Archives of Biochemistry and Biophysics

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The contribution of conformational heterogeneity to cooperativity in cytochrome P450 3A4 was investigated using the mutant L211F/D214E/F304W. Initial spectral studies revealed a loss of cooperativity of the 1-pyrenebutanol (1-PB) induced spin shift (S 50 = 5.4 μM, n = 1.0) but retained cooperativity of α-naphthoflavone binding. Continuous variation (Job's titration) experiments showed the existence of two pools of enzyme with different 1-PB binding characteristics. Monitoring of 1-PB binding by fluorescence resonance energy transfer from the substrate to the heme confirmed that the high affinity site (K D = 0.3 μM) is retained in at least some fraction of the enzyme, although cooperativity is masked. Removal of apoprotein on a second column increased the high spin content and restored cooperativity of 1-PB binding and of progesterone and testosterone 6β-hydroxylation. The loss of cooperativity in the mutant is, therefore, mediated by the interaction of holo-and apo-P450 in mixed oligomers.

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Pharmacogenomics

Melanson

2009

Encyclopedia of Analytical Chemistry

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Adverse drug reactions occur in 5–10% of hospitalized patients and are one of the leading causes of death in the United States. 1, 2 The field of pharmacogenomics explores the relationship between a patient's genetics and his/her response to drugs. If a patient's response to a drug can be predicted by his/her genetics, then the right drug at the right dose can be administered. Additionally, harmful side effects and toxicity can be avoided. Pharmacogenomic genotyping offers the advantage that it only needs to be performed once and can provide unequivocal genetic information. However, the complexity of gene regulation and gene–environment interaction can complicate pharmacogenomic testing. This article provides an overview of pharmacogenomics and examples of pharmacogenomic applications.

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A Single Nucleotide Polymorphism of CYP2B6 Found in Japanese Enhances Catalytic Activity by Autoactivation

Cited by 121 publications

References 17 publications

Role of polymorphic human CYP2B6 in cyclophosphamide bioactivation

Role of polymorphic human CYP2B6 in cyclophosphamide bioactivation

Role of subunit interactions in P450 oligomers in the loss of homotropic cooperativity in the cytochrome P450 3A4 mutant L211F/D214E/F304W

Pharmacogenomics

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