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Detection of MboII Polymorphism at the 5' Promoter Region of CYP3A4,

¹ Department of Clinical and Toxicological Analysis, Faculty of Pharmaceutical Sciences of the Sao Paulo University, Av. Lineu Prestes 580, B17, CEP 05508-900, Sao Paulo, SP, Brazil
^a author for correspondence: fax 55-11-3813-2197, e-mail scavalli@usp.br

	Introduction

 
The P450 cytochromes are a superfamily of hemeproteins that catalyze the metabolism of a large number of xenobiotics and endobiotics. CYP3A4 is the major form of P450 in human liver, metabolizing >50% of all drugs (1). Differences in drug metabolism rates can lead to severe toxicity or therapeutic failure by altering the relationship between dose and blood concentration of the pharmacologically active drug (2). Genetic polymorphisms play a critical role in determining interindividual variation in the expression of several important P450 enzymes (3)(4). Thus, in pharmacogenetic studies, genotyping of polymorphic alleles encoding drug-metabolizing enzymes can be useful for identification of drug metabolism phenotypes (2). Rebbeck et al. (5) have described an adenine-to-guanine (AG) transition at the 5' promoter region (5'PR) of the human CYP3A4 gene (position -290) that is located in a sequence known as the nifedipine-specific element. The variant 5'PR allele was associated with higher clinical stage and grade in men with prostate tumors, possibly because of increased testosterone bioavailability (5). On the other hand, the variant allele was observed to be a protective factor for treatment-related leukemia, whereas the wild-type allele for this polymorphism of CYP3A4 was associated with increased metabolism of epipodophyllotoxin, a chemotherapy agent, leading to leukemias with MLL gene translocations (6). These studies suggest that the variant allele of 5'PR is associated with decreased CYP3A4 expression or decreased activity of the enzyme (5)(6). In contrast, pharmacokinetic studies did not confirm these findings (7)(8).

A high degree . . . [Full Text of this Article]

	Acknowledgments

 

	References

 

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