Feierman Dennis E, Melinkov Zoya, Nanji Amin A
Department of Anesthesiology, The Mount Sinai Medical Center, New York, New York 10029-6574, USA.
Alcohol Clin Exp Res. 2003 Jun;27(6):981-8. doi: 10.1097/01.ALC.0000071738.53337.F4.
Cytochrome P-450 3A (CYP3A) is responsible for the metabolism of numerous therapeutic agents. The content of CYP3A seems to be affected by ethanol ingestion. Because ethanol is used widely, its potential interaction with CYP3A is of great interest. The effects of ethanol on CYP3A content and activity were assessed in different in vivo and in vitro models.
Rats fed either the Lieber-DeCarli ethanol-containing diet or an ethanol and liquid diet via the intragastric tube feeding method were used. Additionally, HepG2 cell lines that constitutively and stably express human CYP3A4 were constructed to study ethanol interactions with CYP3A4.
In all models tested, ethanol induced CYP3A activity and content, as assessed by the metabolism of fentanyl, a sensitive and specific CYP3A substrate, and Western blot analysis, respectively. In the CYP3A4-expressing HepG2 cell line, incubation with ethanol caused a dose-dependent increase in CYP3A4 activity. Ethanol also increased messenger RNA levels of CYP3A4. In the HepG2-CYP3A4 line, incubation with cycloheximide caused a decrease in fentanyl metabolism secondary to a decrease in CYP3A4 levels; this decrease was prevented by coincubation of cycloheximide with ethanol.
Ethanol induced CYP3A activity and content both in vitro and in vivo. There may be multiple mechanisms of induction of CYP3A4 by ethanol, including stabilization of messenger RNA and protein. Ethanol-induced increases in both the protein level and activity of CYP3A4 may play a role that might be of pathophysiological or clinical significance.
细胞色素P-450 3A（CYP3A）负责多种治疗药物的代谢。CYP3A的含量似乎受乙醇摄入的影响。由于乙醇广泛应用，其与CYP3A的潜在相互作用备受关注。在不同的体内和体外模型中评估了乙醇对CYP3A含量和活性的影响。
采用通过胃内管饲法给予含Lieber-DeCarli乙醇饮食或乙醇与流食的大鼠。此外，构建了组成性稳定表达人CYP3A4的HepG2细胞系，以研究乙醇与CYP3A4的相互作用。
在所有测试模型中，通过芬太尼（一种敏感且特异的CYP3A底物）的代谢以及蛋白质印迹分析评估，乙醇诱导了CYP3A活性和含量。在表达CYP3A4的HepG2细胞系中，与乙醇孵育导致CYP3A4活性呈剂量依赖性增加。乙醇还增加了CYP3A4的信使核糖核酸水平。在HepG2-CYP3A4细胞系中，与放线菌酮孵育导致CYP3A4水平降低继发芬太尼代谢减少；放线菌酮与乙醇共同孵育可防止这种降低。
乙醇在体外和体内均诱导CYP3A活性和含量。乙醇诱导CYP3A4可能存在多种机制，包括信使核糖核酸和蛋白质的稳定。乙醇诱导的CYP3A4蛋白质水平和活性增加可能具有病理生理学或临床意义。
