Dataset Information

Functional polymorphisms in xenobiotic metabolizing enzymes and their impact on the therapy of breast cancer.

ABSTRACT: Breast cancer is the top cancer among women, and its incidence is increasing worldwide. Although the mortality tends to decrease due to early detection and treatment, there is great variability in the rates of clinical response and survival, which makes breast cancer one of the most appealing targets for pharmacogenomic studies. The recognition that functional CYP2D6 polymorphisms affect tamoxifen pharmacokinetics has motivated the attempts of using CYP2D6 genotyping for predicting breast cancer outcomes. In addition to tamoxifen, the chemotherapy of breast cancer includes combinations of cytotoxic drugs, which are substrates for various xenobiotic metabolizing enzymes. Because of these drugs' narrow therapeutic window, it has been postulated that impaired biotransformation could lead to increased toxicity. In the present review, we performed a systematic search of all published data exploring associations between polymorphisms in xenobiotic metabolizing enzymes and clinical outcomes of breast cancer. We retrieved 43 original articles involving either tamoxifen or other chemotherapeutic protocols, and compiled all information regarding response or toxicity. The data indicate that, although CYP2D6 polymorphisms can indeed modify tamoxifen pharmacokinetics, CYP2D6 genotyping alone is not enough for predicting breast cancer outcomes. The studies involving other chemotherapeutic protocols explored a great diversity of pharmacogenetic targets, but the number of studies for each functional polymorphism is still very limited, with usually no confirmation of positive associations. In conclusion, the application of pharmacogenetics to predict breast cancer outcomes and to select one individual's chemotherapeutic protocol is still far from clinical routine. Although some very interesting results have been produced, no clear practical recommendations are recognized yet.

SUBMITTER: Vianna-Jorge R

PROVIDER: S-EPMC3551254 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Functional polymorphisms in xenobiotic metabolizing enzymes and their impact on the therapy of breast cancer.

Vianna-Jorge Rosane R Festa-Vasconcellos Juliana Simões JS Goulart-Citrangulo Sheyla Maria Torres SM Leite Marcelo Sobral MS

Frontiers in genetics 20130122

Breast cancer is the top cancer among women, and its incidence is increasing worldwide. Although the mortality tends to decrease due to early detection and treatment, there is great variability in the rates of clinical response and survival, which makes breast cancer one of the most appealing targets for pharmacogenomic studies. The recognition that functional CYP2D6 polymorphisms affect tamoxifen pharmacokinetics has motivated the attempts of using CYP2D6 genotyping for predicting breast cancer ...[more]

PMID: 23346096

Similar Datasets

Project description:BACKGROUND AND PURPOSE:The arylamine N-acetyltransferases (NATs) are xenobiotic-metabolizing enzymes that play an important role in the detoxification and/or bioactivation of arylamine drugs and xenobiotics. In bacteria, NATs may contribute to the resistance against antibiotics such as isoniazid or sulfamides through their acetylation, which makes this enzyme family a possible drug target. Bacillus anthracis, a bacterial species of clinical significance, expresses three NAT isozymes with distinct structural and enzymatic properties, including an inactive isozyme ((BACAN)NAT3). (BACAN)NAT3 features both a non-canonical Glu residue in its catalytic triad and a truncated C-terminus domain. However, the role these unusual characteristics play in the lack of activity of the (BACAN)NAT3 isozyme remains unclear. EXPERIMENTAL APPROACH:Protein engineering, recombinant expression, enzymatic analyses with aromatic amine substrates and phylogenetic analysis approaches were conducted. KEY RESULTS:The deletion of guanine 580 (G580) in the nat3 gene was shown to be responsible for the expression of a truncated (BACAN)NAT3 isozyme. Artificial re-introduction of G580 in the nat3 gene led to a functional enzyme able to acetylate several arylamine drugs displaying structural characteristics comparable with its functional Bacillus cereus homologue ((BACCR)NAT3). Phylogenetic analysis of the nat3 gene in the B. cereus group further indicated that nat3 may constitute a pseudogene of the B. anthracis species. CONCLUSION AND IMPLICATIONS:The existence of NATs with distinct properties and evolution in Bacillus species may account for their adaptation to their diverse chemical environments. A better understanding of these isozymes is of importance for their possible use as drug targets. LINKED ARTICLES:This article is part of a themed section on Drug Metabolism and Antibiotic Resistance in Micro-organisms. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.14/issuetoc.

Dataset Information

Functional polymorphisms in xenobiotic metabolizing enzymes and their impact on the therapy of breast cancer.

Publications

Functional polymorphisms in xenobiotic metabolizing enzymes and their impact on the therapy of breast cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets