Qu’en est-il de l’humain?

chez la souris DT2-DIO. Ils ont démontré qu’il y a une modulation significative de l’activité et de la clairance des cyp450s par l’effet du diabète induit par la diète riche en gras, dont les cyp2c, cyp2d et cyp3a. Par homologie, les sous-familles cyp2c, cyp2d et cyp3a chez la souris correspondent au CYP2C9, CYP2D6 et CYP3A4 chez l’humain, respectivement. Le CYP3A4 hépatique est responsable du métabolisme et de l’élimination de 50%, et avec le CYP2C9 et CYP2D6, l’ensemble de ces trois isoenzymes métabolisent environ 90% des médicaments utilisés en clinique chez l’humain (88, 99, 100, 139, 140). Ce phénomène observé chez la souris DT2-DIO pourrait se produire également chez l’humain. Malgré que l’homologie des cytochromes P450 ne soit pas parfaite entre la souris et l’humain, ce qui demeure une faiblesse incontournable lorsque les études sont effectuées avec des espèces animales, ces travaux permettent d’évaluer si la présence du DT2 peut avoir une influence sur la capacité des CYP450s à métaboliser les médicaments et donc à les éliminer. Ces résultats nous permettent maintenant d’obtenir des données préliminaires supportant l’évaluation de l’impact du DT2 sur les CYP450s chez l’humain.

7 Conclusion

Nos résultats indiquent que le DT2 induit par l’obésité est associé à des changements significatifs de l’expression et de l’activité de plusieurs cyp450s hépatiques et extra-hépatiques chez la souris C57BL/6. En effet, l’activité métabolique de certains cyp450s dont les cyp3a semble être diminuée significativement par le DT2. Également, cette modulation de l’activité des cyp450s chez la souris DT2-DIO était tissu-dépendante. En effet, l’activité des cyp2d semble augmenter au niveau des reins chez la souris DT2-DIO, mais diminuer au niveau des poumons.

Ces résultats présentent une portée clinique importante pour les individus atteints de DT2 et qui possèdent d’autres comorbidités nécessitant une polymédication. En effet, des changements dans l’activité des CYP450s liés à la présence du DT2 pourront avoir un impact majeur sur la pharmacocinétique des médicaments dont le métabolisme s’effectue via ces isoenzymes des CYP450s. De fait, des altérations dans la pharmacocinétique pourront causer des changements dans les concentrations plasmatiques et tissulaires des médicaments chez ces patients et ainsi, les mettre à risque des inefficacités thérapeutiques ou encore à des toxicités médicamenteuses.

Ce profil complet d’expression et d’activité des cyp450s hépatiques et extra-hépatiques obtenu chez la souris C57BL/6 sous diète riche en gras ouvre des pistes de réflexions sur la pharmacocinétique des médicaments chez les personnes atteints de DT2. Des études chez l’humain sont nécessaires afin de mettre en évidence ces impacts sur le changement de la pharmacocinétique dans le contexte de DT2. L’objectif ultime est de mieux comprendre les

diabétiques afin de diminuer la morbidité reliée aux médicaments et d’optimiser leur thérapie. Les résultats de cette étude permettent d’établir des preuves de concept, de réaliser des études chez l’humain afin de confirmer cliniquement ces observations. Dans l’ensemble, nos recherches visent à fournir des outils afin d’optimiser le choix thérapeutique et les dosages médicamenteux appropriés chez les patients diabétiques : une avancée dans l’approche de la médecine personnalisée.

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