title: In-vitro evaluation of chronic alcohol effects on expression of drug-metabolizing and drug-transporting proteins.
abstract: OBJECTIVE
  In alcoholics without alcoholic liver disease, boosted drug elimination has been reported. However, mechanistic explanations for this phenomenon remain uncertain. In particular, data on the potential role of drug transporters are sparse.
  
  
  METHODS
  Using a well-established in-vitro model for induction of human drug-metabolizing and drug-transporting proteins, we evaluated the potency of ethanol and the major fermentation side-product isopentanol to alter expression and function of these proteins by quantitative real-time polymerase chain reaction, Western blotting and flow cytometry. P-glycoprotein (Pgp)-inhibiting properties of ethanol and isopentanol were investigated via calcein extrusion assay.
  
  
  RESULTS
  Ethanol and isopentanol significantly changed expression levels of drug-metabolizing and drug-transporting proteins that normalized within 2 weeks upon withdrawal. Cytochrome P-450 2C19 and Pgp were most strongly induced. Ethanol-induced Pgp at the messenger RNA (mRNA) (twofold to eightfold) and protein level (twofold), but not at the functional level. Both compounds did not inhibit Pgp.
  
  
  CONCLUSIONS
  Ethanol is demonstrated to increase mRNA and protein expression of human drug transporters such as Pgp in vitro. Withdrawal of ethanol exposure causes return to non-induced conditions within weeks. Functional consequences of increased Pgp expression in alcoholics need to be evaluated by clinical trials applying selective Pgp substrates such as digoxin.
authors.affiliation: Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Theile
authors.forename: Tobias T
authors.initials: TT
authors.lastname: Schmidt
authors.forename: Walter E
authors.initials: WE
authors.lastname: Haefeli
authors.forename: Johanna
authors.initials: J
authors.lastname: Weiss
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D027361:Organic Anion Transporters / Q000235:genetics; D000439:Pentanols / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D027361:Organic Anion Transporters; D000439:Pentanols; D000431:Ethanol; D003577:Cytochrome P-450 Enzyme System; C029683:isopentyl alcohol
keywords: LS180; Pgp; alcohol; drug metabolism; drug transporters