Single Mutations in Cytochrome P450 Oxidoreductase Can Alter the Specificity of Human Cytochrome P450 1A2-Mediated Caffeine Metabolism.

A unique cytochrome P450 (CYP) oxidoreductase (CPR) sustains activities of human microsomal CYPs. Its function requires toggling between a closed conformation enabling electron transfers from NADPH to FAD and then FMN cofactors and open conformations forming complexes and transferring electrons to CYPs. We previously demonstrated that distinct features of the hinge region linking the FAD and FMN domain (FD) modulate conformer poses and their interactions with CYPs. Specific FD residues contribute in a CYP isoform-dependent manner to the recognition and electron transfer mechanisms that are additionally modulated by the structure of CYP-bound substrate. To obtain insights into the underlying mechanisms, we analyzed how hinge region and FD mutations influence CYP1A2-mediated caffeine metabolism. Activities, metabolite profiles, regiospecificity and coupling efficiencies were evaluated in regard to the structural features and molecular dynamics of complexes bearing alternate substrate poses at the CYP active site. Studies reveal that FD variants not only modulate CYP activities but surprisingly the regiospecificity of reactions. Computational approaches evidenced that the considered mutations are generally in close contact with residues at the FD-CYP interface, exhibiting induced fits during complexation and modified dynamics depending on caffeine presence and orientation. It was concluded that dynamic coupling between FD mutations, the complex interface and CYP active site exist consistently with the observed regiospecific alterations.

Tympanic Membrane Haematoma in a RivaroxabanTreated Patient: A Case Report.

New generation oral anticoagulants - rivaroxaban, apixaban and edoxaban - represent an important medical achievement. Their therapeutic effectiveness and ease of use make them essential in the management of thromboembolic conditions. However, as warfarin, they have known haemorrhagic risks. This paper reports the case of a 50-year-old female who presented with ear pain and spontaneous blood discharge in her right ear, after a two-week treatment with rivaroxaban. The physical examination revealed a spontaneous tympanic haematoma in the inferior quadrants, adjacent to the umbus. She denied any manipulation of the ear canal. Our goal is to alert for a presumable side effect of this drug in clinical practise.

A nova geração de anti-coagulantes orais ­ rivaroxabano, apixabano e edoxabano ­ constitui um avanço significativo na medicina. Estes fármacos têm, atualmente, um papel fundamental no tratamento de doenças tromboembólicas, pela sua facilidade de administração. No entanto, tal como a varfarina, têm efeitos adversos, nomeadamente aqueles relacionados com o risco hemorrágico. Neste artigo, apresentamos o caso de uma doente de 50 anos de idade, do género feminino, que se apresentou no serviço de urgência com otalgia e otorragia espontânea à direita, após duas semanas de tratamento com rivaroxabano em dose profilática. No exame objetivo, destacava-se a presença de hematoma nos quadrantes inferiores do tímpano, adjacente ao umbus. Não havia história de manipulação do ouvido. O nosso objetivo é alertar para um provável efeito adverso deste fármaco, na prática clínica.