Induction of CYP3A by ethanol in multiple in vitro and in vivo models.

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Citation

Feierman DE, Melinkov Z, Nanji AA

Induction of CYP3A by ethanol in multiple in vitro and in vivo models.

Alcohol Clin Exp Res. 2003 Jun;27(6):981-8. doi: 10.1097/01.ALC.0000071738.53337.F4.

PubMed ID
12824820 [ View in PubMed
]
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.

DrugBank Data that Cites this Article

Drug Enzymes
DrugEnzymeKindOrganismPharmacological ActionActions
EthanolCytochrome P450 3A4ProteinHumans
Unknown
Substrate
Inhibitor
Inducer
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