人肝脏细胞色素P4502B6参与丙泊酚的代谢。
Involvement of human liver cytochrome P4502B6 in the metabolism of propofol.
作者信息
Oda Y, Hamaoka N, Hiroi T, Imaoka S, Hase I, Tanaka K, Funae Y, Ishizaki T, Asada A
机构信息
Department of Anaesthesiology and Intensive Care Medicine, Osaka City University Medical School, Osaka, Japan.
出版信息
Br J Clin Pharmacol. 2001 Mar;51(3):281-5. doi: 10.1046/j.1365-2125.2001.00344.x.
AIMS
To determine the cytochrome P450 (CYP) isoforms involved in the oxidation of propofol by human liver microsomes.
METHODS
The rate constant calculated from the disappearance of propofol in an incubation mixture with human liver microsomes and recombinant human CYP isoforms was used as a measure of the rate of metabolism of propofol. The correlation of these rate constants with rates of metabolism of CYP isoform-selective substrates by liver microsomes, the effect of CYP isoform-selective chemical inhibitors and monoclonal antibodies on propofol metabolism by liver microsomes, and its metabolism by recombinant human CYP isoforms were examined.
RESULTS
The mean rate constant of propofol metabolism by liver microsomes obtained from six individuals was 4.2 (95% confidence intervals 2.7, 5.7) nmol min(-1) mg(-1) protein. The rate constants of propofol by microsomes were significantly correlated with S-mephenytoin N-demethylation, a marker of CYP2B6 (r = 0.93, P < 0.0001), but not with the metabolic activities of other CYP isoform-selective substrates. Of the chemical inhibitors of CYP isoforms tested, orphenadrine, a CYP2B6 inhibitor, reduced the rate constant of propofol by liver microsomes by 38% (P < 0.05), while other CYP isoform-selective inhibitors had no effects. Of the recombinant CYP isoforms screened, CYP2B6 produced the highest rate constant for propofol metabolism (197 nmol min-1 nmol P450-1). An antibody against CYP2B6 inhibited the disappearance of propofol in liver microsomes by 74%. Antibodies raised against other CYP isoforms had no effect on the metabolism of propofol.
CONCLUSIONS
CYP2B6 is predominantly involved in the oxidation of propofol by human liver microsomes.
目的
确定参与人肝微粒体中丙泊酚氧化的细胞色素P450（CYP）同工酶。
方法
由丙泊酚在与人肝微粒体及重组人CYP同工酶的孵育混合物中的消失情况计算出的速率常数，用作丙泊酚代谢速率的指标。研究了这些速率常数与肝微粒体中CYP同工酶选择性底物代谢速率的相关性、CYP同工酶选择性化学抑制剂和单克隆抗体对肝微粒体丙泊酚代谢的影响，以及其在重组人CYP同工酶中的代谢情况。
结果
从6名个体获得的肝微粒体对丙泊酚代谢的平均速率常数为4.2（95%置信区间2.7，5.7）nmol min⁻¹ mg⁻¹蛋白。微粒体对丙泊酚的速率常数与CYP2B6的标志物S-美芬妥因N-去甲基化显著相关（r = 0.93，P < 0.0001），但与其他CYP同工酶选择性底物的代谢活性无关。在所测试的CYP同工酶化学抑制剂中，CYP2B6抑制剂邻苯海明使肝微粒体对丙泊酚的速率常数降低了38%（P < 0.05），而其他CYP同工酶选择性抑制剂无作用。在所筛选的重组CYP同工酶中，CYP2B6对丙泊酚代谢产生的速率常数最高（197 nmol min⁻¹ nmol P450⁻¹）。抗CYP2B6抗体使肝微粒体中丙泊酚的消失减少了74%。针对其他CYP同工酶产生的抗体对丙泊酚代谢无影响。
结论
CYP2B6主要参与人肝微粒体中丙泊酚的氧化。
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