CYP3A activity in African American and European American men: Population differences and functional effect of the CYP3A4*1B 5′-promoter region polymorphism

Wandel, Christoph

doi:10.1067/mcp.2000.108506

Cited by 228 publications

(164 citation statements)

References 29 publications

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“…In the present study, CYP3A4*1B decreased the inducible thiotepa clearance. Other authors have shown that CYP3A4*1B caused a modest decrease in systemic midazolam [38] and ciclosporin clearance [39,40], whereas others did not find an effect [41,42].…”

Section: Discussionmentioning

confidence: 96%

Polymorphisms of drug‐metabolizing enzymes (GST, CYP2B6 and CYP3A) affect the pharmacokinetics of thiotepa and tepa

Ekhart

Doodeman

Rodenhuis

et al. 2008

Brit J Clinical Pharma

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Thiotepa is metabolized by oxidative desulphuration by the cytochrome P450 (CYP) enzymes CYP2B6 and CYP3A4 to tepa. • Furthermore, thiotepa and tepa are conjugated to glutathione, which is catalysed by glutathione S-transferase (GST) isoenzymes A1-1 and P1-1. • Polymorphisms in these enzymes could influence exposure to thiotepa and tepa.• Little is known about the influence of polymorphisms in these enzymes on the pharmacokinetics of thiotepa and tepa. WHAT THIS STUDY ADDS• The presently evaluated variant alleles explain only a small part of the substantial interindividual variability in thiotepa and tepa pharmacokinetics.• We show that probably only the GSTP1 C341T variant allele influences thiotepa exposure to a clinically relevant extent. AIMSThiotepa is widely used in high-dose chemotherapy. Previous studies have shown relations between exposure and severe organ toxicity. Thiotepa is metabolized by cytochrome P450 and glutathione S-transferase enzymes. Polymorphisms of these enzymes may affect elimination of thiotepa and tepa, its main metabolite. The purpose of this study was to evaluate effects of known allelic variants in CYP2B6, CYP3A4, CYP3A5, GSTA1 and GSTP1 genes on pharmacokinetics of thiotepa and tepa. METHODSWhite patients (n = 124) received a high-dose regimen consisting of cyclophosphamide, thiotepa and carboplatin as intravenous infusions. Genomic DNA was analysed using polymerase chain reaction and sequencing. Plasma concentrations of thiotepa and tepa were determined using validated GC and LC-MS/MS methods. Relations between allelic variants and elimination pharmacokinetic parameters were evaluated using nonlinear mixed effects modelling (NONMEM). RESULTSThe polymorphisms CYP2B6 C1459T, CYP3A4*1B, CYP3A5*3, GSTA1 (C-69T, G-52A) and GSTP1 C341T had a significant effect on clearance of thiotepa or tepa. Although significant, most effects were generally not large. Clearance of thiotepa and tepa was predominantly affected by GSTP1 C341T polymorphism, which had a frequency of 9.3%. This polymorphism increased non-inducible thiotepa clearance by 52% [95% confidence interval (CI) 41, 64, P < 0.001] and decreased tepa clearance by 32% (95% CI 29, 35, P < 0.001) in heterozygous patients, which resulted in an increase in combined exposure to thiotepa and tepa of 45% in homozygous patients. CONCLUSIONSThis study indicates that the presently evaluated variant alleles explain only a small part of the substantial interindividual variability in thiotepa and tepa pharmacokinetics. Patients homozygous for the GSTP1 C341T allele may have enhanced exposure to thiotepa and tepa.

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Section: Discussionmentioning

confidence: 96%

Polymorphisms of drug‐metabolizing enzymes (GST, CYP2B6 and CYP3A) affect the pharmacokinetics of thiotepa and tepa

Ekhart

Doodeman

Rodenhuis

et al. 2008

Brit J Clinical Pharma

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“…12 In addition, black men are more likely to possess genetic polymorphisms that favor increased androgen activity such as shorter CAG tri-nucleotide repeats in the androgen receptor gene 13 and a possibly less active variant of the CYP3A4 gene, which encodes a protein involved in the oxidative deactivation of testosterone. 14 Finally, increased androgen activity among black men was suggested by a study which found that benign and malignant prostate tissue from black men had both a greater number of cells staining positive for the androgen receptor as well as more intense staining within positive cells. 15 Although androgens regulate cellular PSA production they also affect prostate size.…”

Section: Discussionmentioning

confidence: 99%

“…Clinical and pathological features of men undergoing radical prostatectomy 146 (18) 84 (20) 1,191 (14) 100 (19) ≥35.0 54 (7) 39 (9) 136 (2) 34 (7) PSA (ng/ml) 0.001 † <0.001 † …”

Section: Tablementioning

confidence: 99%

Do Racial Differences in Prostate Size Explain Higher Serum Prostate-Specific Antigen Concentrations Among Black Men?

Mavropoulos

Partin

Amling

et al. 2007

Urology

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Objectives-Black men have higher serum PSA values than white men. As levels of serum PSA directly correlate with prostate size, we hypothesized that elevated serum PSA values in black men may be due, at least partially, to larger prostate size among black men. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Methods-The NIH Public Access Author ManuscriptUrology. Author manuscript; available in PMC 2012 February 9. at the Johns Hopkins Hospital. We evaluated the association between race and serum PSA and prostate weight using multivariable linear regression while adjusting for demographic and clinicopathological cancer characteristics.Results-In both cohorts, black men had higher serum PSA values (p≤0.001). After adjusting for either demographic characteristics or demographic and cancer-specific characteristics, there were no significant associations between race and prostate size in either cohort. After adjusting for multiple demographic, clinical, and pathological cancer-specific characteristics, black men had 15% higher serum PSA values relative to white men in both the SEARCH (p=0.001) and Hopkins cohorts (p<0.001).Conclusions-In this study of patients undergoing radical prostatectomy in two very different practice settings, black men in both cohorts had higher serum PSA values relative to white men despite adjustment for demographic and cancer-specific characteristics, including prostate weight. The lack of significant association between race and prostate size suggests alternative reasons are needed to explain higher serum PSA levels in black men.

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“…Several studies assessed the risk of SCCHN in relation to CYP or GST genotypes (20 -22). However, interindividual variations in the expression and activity of the CYPs and GST are dependent on genotypic as well as post-transcriptional factors, which maybe tissue specific (23)(24)(25). Therefore, the most direct method to evaluate the effects of CYPs and GST on the carcinogenic effects of tobacco is to evaluate enzyme expression in the tissue of interest.…”

Section: Discussionmentioning

confidence: 99%

Cytochrome P450 and Glutathione Transferase Expression in Squamous Cell Cancer

Ali¹,

El-Rayes²,

Heilbrun³

et al. 2004

Clinical Cancer Research

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Purpose: The cytochrome P-450 (CYP) and glutathione S-transferase (GST) enzyme systems modulate the carcinogenic effects of tobacco. Therefore, the expression of these enzymes may be in part responsible for the observed interindividual and inter-racial differences in the risk of development of squamous cell carcinoma of the head and neck (SCCHN). The first aim of this study was to evaluate the feasibility of measuring the expression of the CYP and GST in target tissue from the head and neck. The second aim was to compare the expression of CYPs 1A1, 2E1, and 3A4 in squamous epithelium from African-American and Caucasian pediatric patients. The third aim was to compare the expression of CYPs 1A1, 2E1, 3A4, and GST-on the p16 expression in patients with SCCHN.Experimental Design: The expression of CYP 1A1, 2E1, 3A4, GST-, and p16 was quantified by immunoblotting. Expression of CYPs 1A1, 2E1, and 3A4 was quantified in tissue from 160 pediatric patients undergoing tonsillectomy. Expression of CYPs 1A1, 2E1, 3A4, GST-, and p16 was determined in 46 resected SCCHN patients.Results: Large interindividual variability in the expression of these enzymes was observed in the pediatric and adult populations. No significant difference was observed in CYP 1A1, 2E1, and 3A4 expression of Caucasian and African-American patients. There was no correlation between p16 and enzyme expression in patients with SCCHN.Conclusion: Evaluation of CYP expression in the target tissue of interest is feasible. The clinical significance of CYPs and GST-alterations in the risk of developing SCCHN will need to be investigated in larger trials.

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CYP3A activity in African American and European American men: Population differences and functional effect of the CYP3A4*1B 5′-promoter region polymorphism

Cited by 228 publications

References 29 publications

Polymorphisms of drug‐metabolizing enzymes (GST, CYP2B6 and CYP3A) affect the pharmacokinetics of thiotepa and tepa

Polymorphisms of drug‐metabolizing enzymes (GST, CYP2B6 and CYP3A) affect the pharmacokinetics of thiotepa and tepa

Do Racial Differences in Prostate Size Explain Higher Serum Prostate-Specific Antigen Concentrations Among Black Men?

Cytochrome P450 and Glutathione Transferase Expression in Squamous Cell Cancer

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