Citocromo P450 2D6: variabilidade na terapêutica e na predisposição para patologias

O Citocromo P450 2D6 (CYP 2D6) é uma importante enzima metabolizadora de fármacos. Apesar de representar apenas 2% do total das isoenzimas CYP, o CYP 2D6 tem um papel importante pois é responsável pela metabolização de cerca de 20 a 25% dos fármacos mais frequentemente utilizados. (Ramamoorthy, 2010) É sabido que nem todos os indivíduos respondem da mesma maneira a um fármaco, podendo alguns sofrer reação adversa devido à toma deste e outros nem apresentar qualquer efeito terapêutico. Tais diferenças na resposta terapêutica devem-se a variações genómicas interindividuais, nos genes que codificam as enzimas responsáveis pelo metabolismo do fármaco. Os alelos polimórficos podem levar a uma redução ou aumento na capacidade metabólica, ao passo que um aumento do número de cópias do gene CYP 2D6 pode conduzir a um aumento da atividade metabólica. Os indivíduos comportam-se de acordo com o seu fenótipo, como metabolizadores lentos, rápidos ou ultra-rápidos (Abraham, 2001) Visto existirem grandes alterações nesta enzima metabolizadora de fármacos, é importante perceber quais as situações onde a segurança e a eficácia estão alteradas, pois qualquer terapêutica tem sempre como base o binómio risco/beneficio. Para além do seu papel bem estabelecido na segurança e eficácia terapêutica, estudos mais recentes relatam que o CYP 2D6 desempenha um papel importante no aparecimento de algumas doenças, condicionando a predisposição individual para patologias, de que é exemplo a esclerose sistémica. (Sanjay Harhang & al, 2001) Como desenvolvimento desta monografia pretende-se estudar os efeitos a nível de segurança e eficácia em determinadas situações terapêuticas e ainda avaliar a associação dos polimorfismos no CYP 2D6 com a predisposição individual para patologias.

Filogeografia de Brachidontes puniceus (Gmelin, 1791) no arquipélago de Cabo Verde

Dissertação mest., Biologia Marinha, Universidade do Algarve, 2009

Liver-like biosensor: immobilized CYP3A4 sensors as tools for ligand binding and enzyme activity measurements

Cytochromes P450 constitute a super-family of enzymes involved in the metabolism of Xenobiotics, where human cytochrome P450 3A4 is the most abundant of all P450s, accounting for about 50% of all human liver cytochromes. This membrane anchored protein is responsible for the metabolization of a wide array of environmental drugs and intoxicants, mainly due to its haem domain properties, and active site cavity volume. These properties make this protein an excellent subject for biosensor application, although CYO3A4 enzyme is also famous for its instability. Enzyme inactivation at room temperature is a normal conversion process that this enzyme undergoes, that may hamper any biosensing approach.

Ecological niche modeling, cytogenetics and phylogeography of the genera Geomalacus and Letourneuxia (Gastropoda, Pulmonata) from the Iberian-Moroccan region

First described more that 150 years ago, the systematics of the genera Geomalacus and Letourneuxia (Arionidae, Gastropoda, Pulmonata) is still challenging. The taxonomic classification of arionid species is based on extremely labile characters such as body size or color that depends both on diet and environment, as well as age. Moreover, there is little information on the genetic diversity and population structure of the Iberian slugs that could provide extra clues to disentangle their problematic classification. The present work uses different analytical tools such as habitat suitability (Ecological Niche Modeling - ENM), cytogenetic analysis and phylogeography to establish the geographical distribution and evolutionary history of these pulmonate slugs. The potential distribution of the four Geomalacus species was modeled using ENM, which allowed the identification of new locations for G. malagensis, including a first report in Portugal. Also, it was predicted a much wider distribution for G. malagensis and G. oliveirae than previously known. Classical cytogenetic analyses were assayed with reproductive and a novel use of somatic tissues (mouth and tentacles) returning the number of chromosomes for the four Geomalacus species and L. numidica (n = 31, 2n = 62) and the respective karyotypes. G. malagensis and L. numidica present similar chromosome morphologies and karyotypic formulae, being more similar to each other than the Geomalacus among themselves. We further reconstructed the phylogeny of the genera Geomalacus and Letourneuxia using partial sequences of the mitochondrial cytochrome oxidase subunit I (COI) and the nuclear ribosomal small subunit (18S rRNA), and applied an independent evolutionary rate method, the indicator vectors correlation, to evaluate the existence of cryptic diversity within species. The five nominal species of Geomalacus and Letourneuxia comprise 14 well-supported cryptic lineages. Letourneuxia numidica was retrieved as a sister group of G. malagensis. G. oliveirae is paraphyletic with respect to G. anguiformis. According to our dating estimates, the most recent common ancestor of Geomalacus dates back to the Middle Miocene (end of the Serravallian stage). The major lineage splitting events within Geomalacus occurred during the dry periods of the Zanclean stage (5.3-3.6 million years) and some lineages were confined to more humid mountain areas of the Iberian Peninsula, which lead to a highly geographically structured mitochondrial genetic diversity. The major findings of this are the following: (1) provides updated species distribution maps for the Iberian Geomalacus expanding the known geographic distribution of the concerned species, (2) unravels the cryptic diversity within the genera Geomalacus and Letourneuxia, (3) Geomalacus oliveirae is paraphyletic with G. anguiformis and (4) Letourneuxia numidica is sister group of G. malagensis.