Induction of CYP3A by Ethanol in Multiple In Vitro and In Vivo Models

Authors


  • Supported by NIH grant R55AA/OD-11320.

  • Presented, in part, at the annual meetings of the Research Society on Alcoholism, Hilton Head, SC, June 1998; the American Society of Anesthesiologists, Orlando, FL, October 1998 and Dallas, TX, October 1999; and the International Anesthesia Research Society, 74th Congress, Honolulu, HI, March 2000.

From the Department of Anesthesiology (DEF, ZM), The Mount Sinai Medical Center, New York, New York; and the Department of Pathology and Laboratory Medicine (AAN), University of Pennsylvania Medical Center, Philadelphia, Pennsylvania.

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

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