Human CYP2C-mediated stereoselective phenytoin hydroxylation in Japanese: difference in chiral preference of CYP2C9 and CYP2C19

Yasumori, Toshio; Chen, Laishun; Li, Qinghua; Ueda, Mitsuharu; Tsuzuki, Toshiharu; Goldstein, Joyce A.; Kato, Ryuichi; Yamazoe, Yasushi

doi:10.1016/s0006-2952(99)00034-9

Cited by 41 publications

(24 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Sz. pombe has previously been used as a host for the expression of microsomal P450s (Yamazaki et al, 1993;Yasumori, 1997Yasumori, , 1999, and the results obtained in those studies as well as this work indicate that the endogenous CPR is capable of reducing heterologously mammalian P450 enzymes. Whole-cell biotransformation experiments using CAD18 demonstrated strong activity of CYP21 expressed in Sz.…”

Section: Discussionsupporting

confidence: 54%

Increased TCA cycle activity and reduced oxygen consumption during cytochrome P450‐dependent biotransformation in fission yeast

Drăgan¹,

Blank²,

Bureik

2006

Yeast

View full text Add to dashboard Cite

Cytochrome P450s are haem-containing monooxygenases that catalyse a variety of oxidations utilizing a large substrate spectrum and are therefore of interest for biotechnological applications. We expressed human CYP21 in fission yeast Schizosaccharomyces pombe as a eukaryotic model for P450-dependent whole-cell biotransformation. The resulting strain displayed strong steroid hydroxylase activity that was accompanied by contrary effects on respiration and non-respiratory oxygen consumption, which combined to a significant decline in total oxygen consumption of the cells. While production of ROS (reactive oxygen species) decreased, the TCA cycle activity increased, as was shown by metabolic flux (METAFoR) analysis. Pentose phosphate pathway (PPP) activity was found to be negligible, regardless of growth phase, CYP21 expression or biocatalytic activity, indicating that NADPH levels in Sz. pombe are sufficiently high to support an exogenous P450 without adaptations of central carbon metabolism. We conclude from these data that neither oxygen supply nor NADPH availability are limiting factors in P450-dependent biocatalysis in Sz. pombe.

show abstract

Section: Discussionsupporting

confidence: 54%

Increased TCA cycle activity and reduced oxygen consumption during cytochrome P450‐dependent biotransformation in fission yeast

Drăgan¹,

Blank²,

Bureik

2006

Yeast

View full text Add to dashboard Cite

show abstract

“…Pooled human liver microsomes were from BD Gentest (Woburn, MA). Racemic 4Ј-HPPH was separated to (S)-and (R)-enantiomers according to a method of Yasumori et al (1999) using a Chiralcel OJ column (4.6 ϫ 250 mm, 10 m; Daicel Chemical, Osaka, Japan). All other chemicals and solvents were of the highest grade commercially available.…”

Section: Methodsmentioning

confidence: 99%

“…4Ј-HPPH has an asymmetric carbon atom. CYP2C9 preferentially catalyzes the formation of the (S)-enantiomer of 4Ј-HPPH, whereas CYP2C19 is not stereoselective (Bajpai et al, 1996;Yasumori et al, 1999). It has been reported that 98% of circulating 4Ј-HPPH after phenytoin administration is the (S)-enantiomer in humans (Ieiri et al, 1995;Yasumori et al, 1999).…”

mentioning

confidence: 99%

“…CYP2C9 preferentially catalyzes the formation of the (S)-enantiomer of 4Ј-HPPH, whereas CYP2C19 is not stereoselective (Bajpai et al, 1996;Yasumori et al, 1999). It has been reported that 98% of circulating 4Ј-HPPH after phenytoin administration is the (S)-enantiomer in humans (Ieiri et al, 1995;Yasumori et al, 1999). 4Ј-HPPH has no anticonvulsant properties, but it is associated with side effects such as gingival hyperplasia, somnolence, dry month, and general fatigue (Ieiri et al, 1992).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Stereoselective Glucuronidation of 5-(4′-Hydroxyphenyl)-5-phenylhydantoin by Human UDP-Glucuronosyltransferase (UGT) 1A1, UGT1A9, and UGT2B15: Effects of UGT-UGT Interactions

Nakajima

Yamanaka²,

Fujiwara³

et al. 2007

Drug Metab Dispos

View full text Add to dashboard Cite

show abstract

“…1 Phenytoin is predominantly metabolized by polymorphic cytochrome P450 CYP2C9 but a minor contribution of CYP2C19 has also been described. 1,2 At least two protein variants (Arg144Cys and lle359Leu) affect 2C9-mediated metabolism of phenytoin 3 and several genetic variants of 2C19 have been reported [4][5][6] with the *2 allele (m1; a splice site mutation) causing the poor metabolizer phenotype in approximately 10% of Caucasians. 5 Population studies have shown that genetic polymorphisms of both CYP2C genes play a important role in the pharmacokinetic variability of phenytoin and that defective 2C9 alleles would increase blood phenytoin levels dramatically and even patients with 2C19 mutations were suggested for careful monitoring at higher daily doses of phenytoin.…”

Section: Introductionmentioning

confidence: 99%

The predictive value of MDR1, CYP2C9, and CYP2C19 polymorphisms for phenytoin plasma levels

et al. 2001

View full text Add to dashboard Cite

Phenytoin, an anticonvulsant, exhibits nonlinear pharmacokinetics with large interindividual differences. Because of its small therapeutic range with the risk of therapeutic failure or adverse drug effects in susceptible persons, therapeutic drug monitoring is frequently applied. The interindividual differences in dose response can partially be explained by known genetic polymorphisms in the metabolic enzyme CYP2C9 but a large deal of individual variability remains still unexplained. Part of this variability might be accounted for by variable uptake of phenytoin, which is a substrate of p-glycoprotein, encoded by the human MDR1 gene. We evaluated, whether phenytoin plasma levels correlate with a polymorphism in the MDR1 gene, C3435T, which is associated with intestinal PGP activity. Genotyping and analyses of plasma levels of phenytoin and metabolites in 96 healthy Turkish volunteers showed that the MDR1C Ͼ T3435 polymorphism affects phenytoin plasma levels (P = 0.064) and the metabolic ratio of p-HPPH vs phenytoin (MDR1*TT genotype, P = 0.026). The MDR1*CC genotype is more common in volunteers with low phenytoin levels (P Յ 0.001, 2 test). A combined analysis of variable alleles of CYP2C9, 2C19 and MDR1 revealed that the number of mutant CYP2C9 alleles is a major determinant, the number of MDR1*T alleles further contributes to the prediction of phenytoin plasma levels and CYP2C19*2 does not explain individual variability. The regression equation that fitted the data best included the number of mutant CYP2C9 and MDR*T alleles as predictory variables and explained 15.4% of the variability of phenytoin data (r 2 = 0.154, P = 0.0002). Furthermore, analysis of CYP2C9 and MDR1 genotypes in 35 phenytoin-treated patients recruited from therapeutic drug monitoring showed that combined CYP2C9 and MDR1 analysis has some predictive value not only in the controlled settings of a clinical trial, but also in the daily clinical practice.

show abstract

Human CYP2C-mediated stereoselective phenytoin hydroxylation in Japanese: difference in chiral preference of CYP2C9 and CYP2C19

Cited by 41 publications

References 24 publications

Increased TCA cycle activity and reduced oxygen consumption during cytochrome P450‐dependent biotransformation in fission yeast

Increased TCA cycle activity and reduced oxygen consumption during cytochrome P450‐dependent biotransformation in fission yeast

Stereoselective Glucuronidation of 5-(4′-Hydroxyphenyl)-5-phenylhydantoin by Human UDP-Glucuronosyltransferase (UGT) 1A1, UGT1A9, and UGT2B15: Effects of UGT-UGT Interactions

The predictive value of MDR1, CYP2C9, and CYP2C19 polymorphisms for phenytoin plasma levels

Contact Info

Product

Resources

About