4β-Hydroxycholesterol is a new endogenous CYP3A marker: relationship to CYP3A5 genotype, quinine 3-hydroxylation and sex in Koreans, Swedes and Tanzanians

Diczfalusy, Ulf; Miura, Jun; Roh, Hyung‐Keun; Mirghani, Rajaa A.; Sayi, Jane; Larsson, Hanna; Bodin, Karl; Allqvist, Annika; Jande, Mary; Kim, Jong-Wook; Aklillu, Eleni; Gustafsson, Lars L.; Bertilsson, Leif

doi:10.1097/fpc.0b013e3282f50ee9

Cited by 139 publications

(177 citation statements)

References 27 publications

Supporting

Mentioning

153

Contrasting

Unclassified

Order By: Relevance

“…The functional CYP3A5 variant allele, CYP3A5*1 is the most frequent variant allele in the black population (B50%) 8,13,16 , whereas in Ethiopians, the defective variant allele (CYP3A5*3) is the most frequent allele (67%). The lower frequency of CYP3A5*1 and absence of the black population-specific allele, CYP3A5*7, differentiate Ethiopians from other black Africans and African Americans with respect to CYP3A5 allele frequency distribution.…”

Section: Discussionmentioning

confidence: 99%

“…Few studies have investigated the genetic polymorphisms in CYP3A5 in African populations. 8,13,16 However, data from these studies cannot be extrapolated to other populations in the continent because Africans are heterogeneous with respect to pharmacogenetics of drug-metabolizing enzymes. 17,18 This study aimed at investigating the influence of CYP3A5 genotype and sex on the CYP3A phenotype and compared the use of plasma 4b-hydroxycholesterol and omeprazole to omeprazole sulfone ratio as CYP3A markers.…”

Section: Introductionmentioning

confidence: 99%

“…7 We recently reported the use of plasma 4b-hydroxycholesterol as a new endogenous CYP3A marker. 8 The relative contribution of CYP3A4 and CYP3A5 to the formation of 4b-hydroxycholesterol or omeprazole sulfone is also not clear but could be estimated by genotypephenotype correlations. In addition, sex differences in the metabolism of some of the CYP3A substrates have been reported but the issue remains controversial.…”

Section: Introductionmentioning

confidence: 99%

“…[9][10][11] Extensive inter-individual and inter-ethnic variability in constitutive CYP3A expression and enzyme activity and hence variations in disposition of CYP3A substrates have been described. 8,[12][13][14] Environmental and genetic factors have significant roles to determine individual variability in CYP expression and enzyme activity. Indeed, CYP3A4 is genetically polymorphic with more than 20 variant alleles described so far.…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Sex and CYP3A5 genotype influence total CYP3A activity: high CYP3A activity and a unique distribution of CYP3A5 variant alleles in Ethiopians

et al. 2010

View full text Add to dashboard Cite

The objectives of the this study were to assess the influence of CYP3A5 genotype and sex on the variability in total CYP3A activity and to compare 4b-hydroxycholesterol and omeprazole sulfoxidation as phenotypic markers for CYP3A activity in Ethiopians. Healthy subjects (n ¼ 150) were genotyped for CYP3A5*3, *6 and *7 using allele-specific PCR and Taqman genotyping assays. Plasma levels of 4b-hydroxycholesterol, 3 h post-dose omeprazole and omeprazole sulfone, were determined by gas chromatography-mass spectrometry and high performance liquid chromatography, respectively. The frequency of CYP3A5*1, *3, *6 and *7 was 20.5, 67.3, 12.2 and 0%, respectively. The mean plasma 4b-hydroxycholesterol level was 35.4 ng ml À1. The mean 4b-hydroxycholesterol level (P ¼ 0.0001) and the 4b-hydroxycholesterol/cholesterol ratio (P ¼ 0.004) were higher in women than in men. CYP3A5 genotype significantly correlated with the plasma 4b-hydroxycholesterol concentration (P ¼ 0.003) and 4b-hydroxycholesterol/ cholesterol ratio (P ¼ 0.0002). The omeprazole/omeprazole sulfone ratio was significantly correlated with 4b-hydroxycholesterol and 4b-hydroxycholesterol/cholesterol ratio in CYP3A5*0/*0 genotypes but not in individuals carrying the CYP3A5*1 allele. No correlation of omeprazole/omeprazole sulfone ratio with sex or CYP3A5 genotype was observed. A clear gene-dose effect implies plasma 4b-hydroxycholesterol level as a useful endogenous biomarker for total CYP3A activity (CYP3A5 plus CYP3A4) whereas the omeprazole/omeprazole sulfone ratio reflects mainly CYP3A4 activity. Sex and CYP3A5 genotype influence total CYP3A activity. Ethiopians display high total CYP3A activity and a unique distribution of CYP3A5 variant alleles not described hitherto.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Sex and CYP3A5 genotype influence total CYP3A activity: high CYP3A activity and a unique distribution of CYP3A5 variant alleles in Ethiopians

et al. 2010

View full text Add to dashboard Cite

show abstract

“…As some differences in CYP3A activity have been observed between different races36, some caution should be used in applying these data more broadly.…”

Section: Discussionmentioning

confidence: 99%

Effect of the CYP3A inhibitors, diltiazem and ketoconazole, on ticagrelor pharmacokinetics in healthy volunteers

Teng

Butler

2013

Journal of Drug Assessment

View full text Add to dashboard Cite

ObjectivesTwo open-label, two-period, crossover studies in healthy volunteers were designed to determine the pharmacokinetic interactions between ticagrelor, a P2Y12 receptor antagonist, and a moderate (diltiazem) and a strong (ketoconazole) cytochrome P450 (CYP) 3A inhibitor.MethodsSeventeen volunteers received diltiazem (240 mg once daily) for 14 days. In the second study, ketoconazole (n = 14) 200 mg twice daily was given for 10 days. A single oral 90-mg ticagrelor dose was administered on day 8 (diltiazem) or day 4 (ketoconazole). In each study, volunteers received a single 90-mg oral dose of ticagrelor before or after washout (≥14 days). Pharmacokinetic parameters for ticagrelor, AR-C124910XX (primary metabolite), diltiazem, and ketoconazole were assessed.ResultsCompared with ticagrelor alone, diltiazem co-administration significantly increased the mean maximum concentration (Cmax) and mean area under the plasma concentration–time curve (AUC) for ticagrelor by 69% and 174%, respectively. Diltiazem co-administration reduced Cmax by 38% but had no significant effect on AUC for AR-C124910XX. Cmax and AUC for ticagrelor were increased by 135% and 632%, respectively, by ketoconazole co-administration, whereas these parameters were reduced by 89% and 56%, respectively, for AR-C124910XX. Diltiazem and ketoconazole pharmacokinetic parameters were not significantly affected by the presence of ticagrelor.ConclusionsThese results suggest that ticagrelor can be co-administered with moderate CYP3A inhibitors. However, co-administration of strong CYP3A inhibitors with ticagrelor is not recommended.

show abstract

Oxysterols: Potential Biomarkers of Oxidative Stress

Iuliano

Diczfalusy

2010

Biomarkers for Antioxidant Defense and Oxidative Damage: Principles and Practical Applications

View full text Add to dashboard Cite

4β-Hydroxycholesterol is a new endogenous CYP3A marker: relationship to CYP3A5 genotype, quinine 3-hydroxylation and sex in Koreans, Swedes and Tanzanians

Cited by 139 publications

References 27 publications

Sex and CYP3A5 genotype influence total CYP3A activity: high CYP3A activity and a unique distribution of CYP3A5 variant alleles in Ethiopians

Sex and CYP3A5 genotype influence total CYP3A activity: high CYP3A activity and a unique distribution of CYP3A5 variant alleles in Ethiopians

Effect of the CYP3A inhibitors, diltiazem and ketoconazole, on ticagrelor pharmacokinetics in healthy volunteers

Oxysterols: Potential Biomarkers of Oxidative Stress

Contact Info

Product

Resources

About