S. Pilote, A. Kamaliza, A. Blais-Boilard, D. Patoine, B. Drolet, C. Simard; Institut Universitaire de Cardiologie et de Pneumologie de Quebec, Quebec City, QC, Canada
BACKGROUND: Most patients with type I (T1D) and type II (T2D) diabetes are treated with multiple drugs. Evidence suggests that drug disposition is altered in T1D and T2D. We have already demonstrated that in mouse, hepatic activity of CYP3a is increased in both T1D and T2D. We then hypothesized that hepatic expression of CYP2c and CYP4a, catalyzing biotransformation of xenobiotics and endogenous substrates such as arachidonic acid (AA), is also modulated by T1D and/or T2D.
METHODS: Mouse models of T1D (streptozotocin) and T2D (C57BLKS/J-db/db) were used in this study. After sacrifice, livers were collected, washed in cold PBS and snap frozen. Total proteins were extracted using ice-cold lysis buffer. Western blots were performed to assess CYP2c and CYP4a protein expression.
RESULTS: Our results showed a significant decrease in relative protein expression of hepatic CYP2c in T2D (1.55±0.16, n=19, p<0.05) compared to control (2.21±0.19, n=17). A significant increase was observed in relative protein expression of hepatic CYP4a in both TD1 and TD2 groups (0.92±0.06, n=19, p<0.001; 1.06±0.40, n=19, p<0.001, respectively) compared to control (0.18±0.01, n=17).
CONCLUSION: This study shows that disease conditions such as T1D and T2D alter protein expression of cytochromes P450, likely affecting drug metabolism and disposition and leading to various clinical consequences in patients suffering from diabetes and exposed to CYP2C substrates such as warfarin. Moreover, these alterations could induce disturbances in the endogenous pathway (CYP450) of AA metabolism and increase the risk of cardiovascular disease by disrupting the fine equilibrium between cardioprotective (CYP2C-generated) and cardiotoxic (CYP4A-generated) metabolites of AA and pushing the balance towards the cardiotoxic side.