Modulation of cytochrome P-450 dependent monooxygenases in streptozotocin-induced diabetic hamster: I. Effects of propofol on defluorination and cytochrome P-450 activities.
BACKGROUND
Diabetes mellitus could induce polymorphic alterations of metabolic activities of cytochrome P-450 dependent monooxygenases in chemical-induced diabetic animals. The purpose of this study is to define the functional impact of clinical concentrations of propofol on the metabolic activities of cytochrome P-450 in the diabetic animals.


METHODS
In order to validate the effect of propofol on cytochrome P-450 activities, especially the cytochrome P-450 2E1 and its defluorination activity, we applied NADPH-generating system to measure the metabolizing activities of cytochrome P-450 isozymes of streptozotocin-induced diabetic hamsters within the microsomes preincubated with various concentrations of propofol. The extent of defluorination and activity of cytochrome P-450 2E1 were assessed by reacting the propofol-treated microsomes in NADPH-generating system with enflurane and aniline as substrates respectively. Drug metabolizing activities of cytochrome 1A1, 2B1, and 3A4 were evaluated by metabolizing specific substrates, benzo(a)pyrene, pentoxyresorufin and erythromycin, within the microsomes of diabetic hamsters preincubated with various concentrations of propofol.


RESULTS
The hepatic and renal defluorination of enflurane was significantly inhibited by 0.05 and 0.10 mM propofol in the microsomes of diabetic hamster (P < 0.05). The activities of aniline hydroxylase (cytochrome 2E1), pentoxyresorufin O-dealkylase (cytochrome 2B1) and benzo(a)pyrene hydroxylase (cytochrome 1A1) were inhibited by propofol in a concentration-dependent manner from 0.05 to 0.10 mM. However, propofol showed no significant effect to the erythromycin N-demethylase (cytochrome 3A4) at its concentration of 0.05-0.10 mM in the diabetic hamsters.


CONCLUSIONS
Our data demonstrated that propofol in therapeutic concentrations of 0.05 and 0.10 mM, could inhibit both liver and kidney defluorination and cytochrome P-450's activities of the diabetic hamsters in vitro of different extent. This should remind clinicians of propofol's potential drug-to-drug interactions in the diabetic patients.
Chen
T L
TL
Department of Anesthesiology, Taipei Medical College, Wan-Fang Hospital, Taiwan.
Chang
H C
HC
Chen
T G
TG
Tai
Y T
YT
Chen
R M
RM
D000818:Animals; D006224:Cricetinae; D019392:Cytochrome P-450 CYP2E1 / Q000502:physiology; D065607:Cytochrome P-450 Enzyme Inhibitors; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D004347:Drug Interactions; D004737:Enflurane / Q000378:metabolism*; D005461:Fluorine / Q000378:metabolism; D008297:Male; D008647:Mesocricetus; D015742:Propofol / Q000494:pharmacology*; D013311:Streptozocin
D065607:Cytochrome P-450 Enzyme Inhibitors; D005461:Fluorine; D013311:Streptozocin; D004737:Enflurane; D019392:Cytochrome P-450 CYP2E1; D015742:Propofol