Potential inhibition of cytochrome P450 3A4 by propofol in human primary hepatocytes.
OBJECTIVE
Hepatic cytochrome P450 isoenzymes constitute a superfamily of hemoproteins that play a major role in the metabolism of endogenous compounds and in the detoxification of xenobiotic molecules. P450 3A4 is one of the most important forms in human being, and mediates the metabolism of around 70 % of therapeutic drugs and endogenous compounds. Propofol, a widely used intravenous anesthetic drug, is known to inhibit cytochrome P450 activities in isolated rat hepatocytes. The goal of this study was to evaluate the potential efficacy of propofol on P450 3A4 in a dose-dependent manner to understand its drug-drug interaction.


METHODS
Hepatocytes were isolated from liver specimens from hepatic angioma patients undergone hepatic surgery. Primary incubated hepatocytes were treated with 0, 0.01, 0.05, 0.1, 0.5, and 1.0 mM propofol for 24 hours. P450 3A4 activity was measured with Nash's colorimetry. The protein expression was assessed by Western blot analysis.


RESULTS
A dose-dependent inhibitory effect of propofol was observed in cytochrome P450 3A4 activity. A minimal dosage of propofol (0.01 mM) induced a significant inhibition of P450 3A4 activity, although its regular dosages (0.01-0.1 mM) showed no inhibitory effect on the cellular protein expression of P450 3A4.


CONCLUSIONS
Propofol may be a potential CYP3A4 inhibitor as this anesthetic can inhibit isoenzyme activity significantly and reduce the metabolic rate of CYP3A4 substrates. This inhibition occurs at post-expression level, and concentration of propofol used clinically does not affect CYP3A4 protein expression. propofol may thus induce drug interaction of cytochrome P450 3A4 activity at the dosage used clinically.
Yang
Li-Qun
LQ
Department of Anesthesiology, Eastern Hepatobiliary Surgery Hospital, the Second Military Medical University, Shanghai 200438, China.
Yu
Wei-Feng
WF
Cao
Yun-Fei
YF
Gong
Bin
B
Chang
Qing
Q
Yang
Guang-Shun
GS
D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors*; D002478:Cells, Cultured; D051544:Cytochrome P-450 CYP3A; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D022781:Hepatocytes / Q000201:enzymology*; D006801:Humans; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors*; D015742:Propofol / Q000008:administration & dosage / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D015742:Propofol