Modélisation des relations entre un aquifère alluvial et une rivière : application au Ried de Colmar (Alsace-France)

Dans cette communication sont présentés les résultats des modélisations effectuées dans le Ried de Colmar (plaine d'Alsace) en vue d'étudier les échanges existants entre la rivière Ill et la nappe phréatique rhénane. Dans les secteurs de Ried, l'affleurement des eaux souterraines se traduit par d'importants échanges avec le réseau hydrographique constitué par l'Ill et des cours d'eau drainant l'aquifère : les rivières phréatiques. L'analyse des données piézométriques et hydrométriques collectées durant les années hydrologiques 1985-86 et 1986-87 a mis en évidence le rôle respectif des différents éléments du sytème. En période de basses eaux l'aquifère assure une bonne partie de l'alimentation des cours d'eaux, alors qu'en période de hautes eaux, les flux s'inversent et l'aquifère lamine une partie des débits de crue. Afin de quantifier et de localiser les échanges nappe-rivières, un modèle mathématique de simulation a été employé. Le modèle CANARI qui est présenté est composé d'un module de calcul d'écoulement à suface libre et d'un modèle de calcul de l'hydrodynamique de l'aquifère. Son utilisation a permis d'affiner des secteurs de drainage et d'alimentation de l'aquifère. (Résumé d'auteur

The Central Role of Cytochrome P450 in Xenobiotic Metabolism—A Brief Review on a Fascinating Enzyme Family

Funding: The elaboration of this manuscript was in part funded by grant UID/BIM/0009/2020 of the Portuguese Fundação para a Ciência e a Tecnologia (FCT) for the Research Center for Toxicogenomics and Human Health (ToXomics).publishersversionpublishe

Pleiotropy of Progesterone Receptor Membrane Component 1 in Modulation of Cytochrome P450 Activity.

Progesterone receptor membrane component 1 (PGRMC1) is one of few proteins that have been recently described as direct modulators of the activity of human cytochrome P450 enzymes (CYP)s. These enzymes form a superfamily of membrane-bound hemoproteins that metabolize a wide variety of physiological, dietary, environmental, and pharmacological compounds. Modulation of CYP activity impacts the detoxification of xenobiotics as well as endogenous pathways such as steroid and fatty acid metabolism, thus playing a central role in homeostasis. This review is focused on nine main topics that include the most relevant aspects of past and current PGRMC1 research, focusing on its role in CYP-mediated drug metabolism. Firstly, a general overview of the main aspects of xenobiotic metabolism is presented (I), followed by an overview of the role of the CYP enzymatic complex (IIa), a section on human disorders associated with defects in CYP enzyme complex activity (IIb), and a brief account of cytochrome b5 (cyt b5)'s effect on CYP activity (IIc). Subsequently, we present a background overview of the history of the molecular characterization of PGRMC1 (III), regarding its structure, expression, and intracellular location (IIIa), and its heme-binding capability and dimerization (IIIb). The next section reflects the different effects PGRMC1 may have on CYP activity (IV), presenting a description of studies on the direct effects on CYP activity (IVa), and a summary of pathways in which PGRMC1's involvement may indirectly affect CYP activity (IVb). The last section of the review is focused on the current challenges of research on the effect of PGRMC1 on CYP activity (V), presenting some future perspectives of research in the field (VI)

Interaction modes of microsomal cytochrome p450s with its reductase and the role of substrate binding

The activity of microsomal cytochromes P450 (CYP) is strictly dependent on the supply of electrons provided by NADPH cytochrome P450 oxidoreductase (CPR). The variant nature of the isoform-specific proximal interface of microsomal CYPs implies that the interacting interface between the two proteins is degenerated. Recently, we demonstrated that specific CPR mutations in the FMN-domain (FD) may induce a gain in activity for a specific CYP isoform. In the current report, we confirm the CYP isoform dependence of CPR’s degenerated binding by demonstrating that the effect of four of the formerly studied FD mutants are indeed exclusive of a specific CYP isoform, as verified by cytochrome c inhibition studies. Moreover, the nature of CYP’s substrate seems to have a modulating role in the CPR:CYP interaction. In silico molecular dynamics simulations of the FD evidence that mutations induces very subtle structural alterations, influencing the characteristics of residues formerly implicated in the CPR:CYP interaction or in positioning of the FMN moiety. CPR seems therefore to be able to form effective interaction complexes with its structural diverse partners via a combination of specific structural features of the FD, which are functional in a CYP isoform dependent manner, and dependent on the substrate bound.publishersversionpublishe

The Complex Dynamic of Phase I Drug Metabolism in the Early Stages of Doxorubicin Resistance in Breast Cancer Cells

Funding: This research was partly funded by the Research Center grant ToxOmics (UIDB/00009/2020 and UIDP/0009/2020), from the Portuguese Fundação para a Ciência e a Tecnologia—FCTThe altered activity of drug metabolism enzymes (DMEs) is a hallmark of chemotherapy resistance. Cytochrome P450s (CYPs), mainly CYP3A4, and several oxidoreductases are responsible for Phase I metabolism of doxorubicin (DOX), an anthracycline widely used in breast cancer (BC) treatment. This study aimed to investigate the role of Phase I DMEs involved in the first stages of acquisition of DOX-resistance in BC cells. For this purpose, the expression of 92 DME genes and specific CYP-complex enzymes activities were assessed in either sensitive (MCF-7 parental cells; MCF-7/DOXS) or DOX-resistant (MCF-7/DOXR) cells. The DMEs genes detected to be significantly differentially expressed in MCF-7/DOXR cells (12 CYPs and eight oxidoreductases) were indicated previously to be involved in tumor progression and/or chemotherapy response. The analysis of CYP-mediated activities suggests a putative enhanced CYP3A4-dependent metabolism in MCF-7/DOXR cells. A discrepancy was observed between CYP-enzyme activities and their corresponding levels of mRNA transcripts. This is indicative that the phenotype of DMEs is not linearly correlated with transcription induction responses, confirming the multifactorial complexity of this mechanism. Our results pinpoint the potential role of specific CYPs and oxidoreductases involved in the metabolism of drugs, retinoic and arachidonic acids, in the mechanisms of chemo-resistance to DOX and carcinogenesis of BC.publishersversionpublishe