Jose Rueff

Publications (169) See all

• Journal Article: Functional characterization of eight human CYP1A2 variants: the role of cytochrome b5.

  Bernardo B Palma, Marta Silva E Sousa, Phillipe Urban, José Rueff, Michel Kranendonk

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  ABSTRACT: Interindividual variability in cytochrome P450 (CYP)-mediated xenobiotic metabolism is extensive. CYP metabolism requires two electrons, which can be donated by NADPH cytochrome P450 oxidoreductase (CYPOR) and/or cytochrome b5 (b5). Although substantial number of studies have reported on the function and effect of b5 in CYP-mediated catalysis, its mode of action is still not fully understood. The aim of this work was to examine the effect of b5 on the activities of eight natural-occurring variants of human CYP1A2, namely, T83M, S212C, S298R, G299S, I314V, I386F, C406Y, and R456H. An approach, as used in our former study was applied, coexpressing these polymorphic CYP1A2 variants separately with CYPOR and b5 in the bacterial cell model BTC-CYP. For each variant, 16 different activity parameters were measured, using eight different substrates. This heterogeneous data set was merged with the one of our former study (i.e. without b5) and a multivariate analysis was carried out. This analysis indicated that b5 seems to have the ability to affect CYP1A2 variants to behave more like the wild-type variant. This was especially the case for variant I386F, for which the presence of b5 was crucial to show activity. Variants T83M and C406Y showed considerably different activity-profiles when in the presence of b5. Furthermore, our data seem to implicate CYP1A2 residue G299 in its interaction with CYPOR and/or b5. Results indicate the ability of b5 to affect CYP1A2 variants to behave more like the wild-type variant, attenuating detrimental effects of structural mutations of these variants, seemingly through extensive allosteric effects.

  Pharmacogenetics and genomics. 02/2013; 23(2):41-52. · 3.49 Impact Factor
• Source

  Available from: Celia Martins

  Dataset: Rodrigues,2012-Genomics and Cancer Drug Resistance

  Antonio S Rodrigues, Joana Dinis, Marta Gromicho, Celia Martins, Antonio Laires, Jose Rueff
• Source

  Available from: Marta Gromicho

  Journal Article: Instability of mRNA expression signatures of drug transporters in chronic myeloid leukemia patients resistant to imatinib.

  Marta Gromicho, Marta Magalhães, Fátima Torres, Joana Dinis, Alexandra R Fernandes, Paula Rendeiro, Purificação Tavares, António Laires, José Rueff, António Sebastião Rodrigues

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  ABSTRACT: Despite the success of imatinib mesylate (IM) in the treatment of chronic myeloid leukemia (CML), approximately 30% of patients are resistant to therapy, mostly due to unknown causes. To profile the expression signatures of drug transporters throughout IM therapy and correlate them with resistance, we quantified mRNA expression levels of the SLC22A12, ABCB1, ABCC1, ABCG2 and MVP genes in consecutive samples from peripheral blood or bone marrow of CML patients who were either responsive or resistant to IM. Additionally we identified and quantified BCR-ABL1 transcript variants and analyzed 1236T>C ABCB1 and 480G>C SLC22A1 polymorphisms. A relationship between the type of BCR-ABL1 transcript or ABCB1 or SLC22A1 genotype and response to treatment was not discovered. However, the studied genes had higher expression levels in follow-up compared to the diagnostic samples, demonstrating a possible induction in expression. IM-sensitive patients presented significantly higher values of SLC22A1 expression, suggesting higher drug influx. Most importantly, while responding patients demonstrated stable expression signatures in consecutive samples, there was considerable variation in IM-resistant patients, indicating that single point sampling expression signatures are not reliable in predicting clinical outcomes or prognostic features in these patients. Studies that assessed consecutive samples from CML patients in order to evaluate the variation in expression levels of transporter genes are limited yet our study emphasizes the importance of such approaches.

  Oncology reports. 11/2012; · 1.84 Impact Factor
• Journal Article: Three New Labdanes Isolated from Eragrostis viscosa

  N'Soki N. Sebastião, Nelson Fernandes, Liliana Vieira, António J. G. Mendonça, Jorge F. Gaspar, Celia Martins, José Rueff, Carlos Diakanamwa and Dina I. M. D. de Mendonça

  Journal of the Brazilian Chemical Society. 11/2012; 23(10):1940. · 1.43 Impact Factor
• Journal Article: Polymorphisms in base excision repair genes and thyroid cancer risk.

  Luís S Santos, Sandra C Branco, Susana N Silva, Ana Paula Azevedo, Octávia M Gil, Isabel Manita, Teresa C Ferreira, Edward Limbert, José Rueff, Jorge F Gaspar

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  ABSTRACT: Thyroid cancer (TC) is the most frequent endocrine malignancy, accounting however for only 1-2% of all human cancers, and the best-established risk factor for TC is radiation exposure, particularly during childhood. Since the BER pathway seems to play an important role in the repair of DNA damage induced by IR and other genotoxicants, we carried out a hospital-based case-control study in order to evaluate the potential modifying role of 6 BER polymorphisms on the individual susceptibility to non-familial TC in 109 TC patients receiving iodine-131, and 217 controls matched for age (±2 years), gender and ethnicity. Our results do not reveal a significant involvement of XRCC1 Arg194Trp and Arg399Gln, OGG1 Ser326Cys, APEX1 Asp148Glu, MUTYH Gln335His and PARP1 Val762Ala polymorphisms on the individual susceptibility towards TC, mostly in aggreement with the limited available evidence. By histological stratification analyis, we observed that the association between the presence of heterozygozity in the MUTYH Gln335His polymorphism and TC risk almost reached significance for the papillary subtype of TC. This was the first time that the putative association between this polymorphism and TC susceptibility was evaluated. However, since the sample size was modest, the possibility of a type I error should not be excluded and this result should, therefore, be interpreted with caution. More in depth studies involving larger populations should be pursued in order to further clarify the potential usefulness of the MUTYH Gln335His genotype as a predictive biomarker of susceptibility to TC and the role of the remaining BER polymorphisms on TC susceptibility.

  Oncology reports. 08/2012; 28(5):1859-68. · 1.84 Impact Factor