CYP3A4 promoter variant is associated with prostate cancer risk in men with benign prostate hyperplasia

Tayeb, Mohammed T.; Clark, Caroline; Sharp, Linda; Haites, Neva Elizabeth; Rooney, Patrick H.; Murray, Graeme I.; Payne, Simon; McLeod, Howard L.

doi:10.3892/or.9.3.653

Cited by 28 publications

(26 citation statements)

References 7 publications

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“…The only allele that appears to influence the CYP3A4 expression is CYP3A4*1B, common in Africans and present at 5% frequency in Caucasians, through alteration of nuclear proteins binding to the polymorphic element . The distribution of the CYP3A4*1B allele has been associated to prostate and lung cancer, although the data are generally conflicting (Rebbeck et al, 1998;Paris et al, 1999;Spurdle et al, 2002;Tayeb et al, 2002Tayeb et al, , 2003Dally et al, 2003). The basis for any genetic background for the interindividual variation in CYP3A4 expression remains a challenge.…”

Section: Cyp3a4/5mentioning

confidence: 99%

Cytochrome P450 pharmacogenetics and cancer

2006

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The cytochromes P450 (CYPs) are key enzymes in cancer formation and cancer treatment. They mediate the metabolic activation of numerous precarcinogens and participate in the inactivation and activation of anticancer drugs. Since all CYPs that metabolize xenobiotics are polymorphic, much emphasis has been put on the investigation of a relationship between the distribution of specific variant CYP alleles and risk for different types of cancer, but a consistent view does not yet exist. This is to a great extent explained by the fact that the CYPs involved in activation of precarcinogens are in general not functionally polymorphic. This is in contrast to CYPs that are active in drug biotransformation where large interindividual differences in the capacity to metabolize therapeutic drugs are seen as a consequence of polymorphic alleles with altered function. This includes also some anticancer drugs like tamoxifen and cyclophosphamide metabolized by CYP2D6, CYP2C19 and CYP2B6. Some P450 forms are also selectively expressed in tumours, and this could provide a mechanism for drug resistance, but also future therapies using these enzymes as drug targets can be envisioned. This review gives an upto-date description of our current knowledge in these areas.

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Section: Cyp3a4/5mentioning

confidence: 99%

Cytochrome P450 pharmacogenetics and cancer

2006

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“…21 G/G homozygotes lack CYP3A5 expression, whereas individuals with at least one wild-type allele (A/A or A/G) express CYP3A5. 21 A common A>G transition in the 5′ regulatory region of CYP3A4 (CYP3A4*1B, rs2740574) has been associated with prostate cancer risk [23][24][25] and may also moderately increase CYP3A4 activity, 26 though a substantial effect of this SNP on the hepatic expression of CYP3A4 has not been demonstrated. [27][28][29][30] These two polymorphisms are linked.…”

Section: Introductionmentioning

confidence: 99%

Pharmacogenomic and Pharmacokinetic Determinants of Erlotinib Toxicity

Rudin

Desai

et al. 2008

JCO

203

156

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Purpose-To assess the pharmacogenomic and pharmacokinetic determinants of skin rash and diarrhea, the two primary dose-limiting toxicities of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTERESTAlthough all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership HHS Public Access Author Manuscript Author ManuscriptAuthor Manuscript Author ManuscriptPatients and Methods-A prospective clinical study of 80 patients with non-small-cell lung cancer, head and neck cancer, and ovarian cancer was performed. Detailed pharmacokinetics and toxicity of erlotinib were assessed. Polymorphic loci in EGFR, ABCG2, CYP3A4, and CYP3A5were genotyped, and their effects on pharmacokinetics and toxicities were evaluated.Results-A novel diplotype of two polymorphic loci in the ABCG2 promoter involving −15622C/T and 1143C/T was identified, with alleles conferring lower ABCG2 levels associated with higher erlotinib pharmacokinetic parameters, including area under the curve (P = .019) and maximum concentration (P = .006). Variability in skin rash was best explained by a multivariate logistic regression model incorporating the trough erlotinib plasma concentration (P = .034) and the EGFR intron 1 polymorphism (P = .044). Variability in diarrhea was associated with the two linked polymorphisms in the EGFR promoter (P < .01), but not with erlotinib concentration.Conclusion-Although exploratory in nature, this combined pharmacogenomic and pharmacokinetic model helps to define and differentiate the primary determinants of skin and gastrointestinal toxicity of erlotinib. The findings may be of use both in designing trials targeting a particular severity of rash and in considering dose and schedule modifications in patients experiencing dose-limiting toxicities of erlotinib or similarly targeted agents. Further studies of the relationship between germline polymorphisms in EGFR and the toxicity and efficacy of EGFR inhibitors are warranted.

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“…28 Men who are homozygote carriers of the CYP3A4*1B variant are at more significant risk of prostate cancer at a higher stage and grade. 27,28 (Table 1). CYP2C8*2 variant may have the potential implication for the metabolism of a number of therapeutic agents, such as amodiaquine, dapsone, ibuprofen and morphine on the GEML.…”

Section: Pharmacogenetics In Ghanamentioning

confidence: 99%

“…CYP3A4*1B variant has also been associated with various diseases such as breast and prostate cancer. 27 , treatment related leukaemia. 28 Men who are homozygote carriers of the CYP3A4*1B variant are at more significant risk of prostate cancer at a higher stage and grade.…”

Section: Pharmacogenetics In Ghanamentioning

confidence: 99%