Potential inhibition of cytochrome P450 3A4 by propofol in human primary hepatocytes

来源 :World Journal of Gastroenterology | 被引量 : 0次 | 上传用户:xhbing520
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AIM:Hepatic cytochrome P450 isoenzymes constitute asuperfamily of hemoproteins that play a major role in themetabolism of endogenous compounds and in thedetoxification of xenobiotic molecules.P450 3A4 is one ofthe most important forms in human being,and mediatesthe metabolism of around 70 % of therapeutic drugs andendogenous compounds.Propofol,a widely used intravenousanesthetic drug,is known to inhibit cytochrome P450activities in isolated rat hepatocytes.The goal of this studywas to evaluate the potential efficacy of propofol on P4503A4 in a dose-dependent manner to understand its drug-drug interaction.METHODS:Hepatocytes were isolated from liver specimensfrom 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 3A4activity was measured with Nash’s colorimetry.The proteinexpression was assessed by Western blot analysis.RESULTS:A dose-dependent inhibitory effect of propofolwas observed in cytochrome P450 3A4 activity.A minimaldosage of propofol(0.01 raM)induced a significant inhibitionof P450 3A4 activity,although its regular dosages(0.01-0.1raM)showed no inhibitory effect on the cellular proteinexpression of P450 3A4.CONCLUSION:Propofol may be a potential CYP3A4 inhibitoras this anesthetic can inhibit isoenzyme activity significantlyand reduce the metabolic rate of CYP3A4 substrates.Thisinhibition occurs at post-expression level,and concentrationof propofol used clinically does not affect CYP3A4 proteinexpression,propofol may thus induce drug interaction ofcytochrome P450 3A4 activity at the dosage used clinically. AIM: Hepatic cytochrome P450 isoenzymes constitutes as uperfamily of hemoproteins that play a major role in themetabolism of endogenous compounds and in the detoxification of xenobiotic molecules. P450 3A4 is one of the most important forms in human being, and mediatesthe metabolism of around 70% of therapeutic drugs andendogenous compounds. Propofol, a widely used intravenousanesthetic drug, is known to inhibit cytochrome P450activities in isolated rat hepatocytes. The goal of this study was to evaluate the potential efficacy of propofol on P4503A4 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. by Western blot analysis .RESULTS: A dose-dependent inhibitory effect of propofolwas obser ved in cytochrome P450 3A4 activity. A minimaldosage of propofol (0.01 raM) induced a significant inhibition of P450 3A activity, although its regular dosages (0.01-0.1raM) showed no inhibitory effect on the cellular proteine ​​expression of P450 3A4.CONCLUSION: Propofol may be a potential CYP3A4 inhibitoras 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 proteinexpression, propofol may therefore induce drug interaction of cytochrome P450 3A4 activity at the dosage used clinically.
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