title: Antiepileptic drugs increase plasma levels of 4beta-hydroxycholesterol in humans: evidence for involvement of cytochrome p450 3A4.
abstract: The major cholesterol oxidation products in the human circulation are 27-hydroxycholesterol, 24-hydroxycholesterol, and 7alpha-hydroxycholesterol. These oxysterols are formed from cholesterol by specific cytochrome P450 enzymes, CYP27, CYP46, and CYP7A, respectively. An additional oxysterol present in concentrations comparable with 7alpha- and 24-hydroxycholesterol is 4beta-hydroxycholesterol. We now report that patients treated with the antiepileptic drugs phenobarbital, carbamazepine, or phenytoin have highly elevated levels of plasma 4beta-hydroxycholesterol. When patients with uncomplicated cholesterol gallstone disease were treated with ursodeoxycholic acid, plasma 4beta-hydroxycholesterol increased by 45%. Ursodeoxycholic acid, as well as the antiepileptic drugs, are known to induce cytochrome P450 3A. Recombinant CYP3A4 was shown to convert cholesterol to 4beta-hydroxycholesterol, whereas no conversion was observed with CYP1A2, CYP2C9, or CYP2B6. The concentration of 4alpha-hydroxycholesterol in plasma was lower than the concentration of 4beta-hydroxycholesterol and not affected by treatment with the antiepileptic drugs or ursodeoxycholic acid. Together, these data suggest that 4beta-hydroxycholesterol in human circulation is formed by a cytochrome P450 enzyme.
authors.affiliation: Department of Medical Laboratory Sciences and Technology, Karolinska Institutet, Huddinge University Hospital, SE-141 86 Huddinge, Sweden.
authors.forename: K
authors.initials: K
authors.lastname: Bodin
authors.forename: L
authors.initials: L
authors.lastname: Bretillon
authors.forename: Y
authors.initials: Y
authors.lastname: Aden
authors.forename: L
authors.initials: L
authors.lastname: Bertilsson
authors.forename: U
authors.initials: U
authors.lastname: Broomé
authors.forename: C
authors.initials: C
authors.lastname: Einarsson
authors.forename: U
authors.initials: U
authors.lastname: Diczfalusy
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D002220:Carbamazepine / Q000494:pharmacology; D002460:Cell Line; D002756:Cholagogues and Choleretics / Q000494:pharmacology; D002784:Cholesterol / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D006888:Hydroxycholesterols / Q000097:blood*; D007313:Insecta; D007700:Kinetics; D008297:Male; D008861:Microsomes / Q000378:metabolism; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D010634:Phenobarbital / Q000494:pharmacology; D010672:Phenytoin / Q000494:pharmacology; D011994:Recombinant Proteins / Q000378:metabolism; D014580:Ursodeoxycholic Acid / Q000494:pharmacology
chemical_list: D000927:Anticonvulsants; D002756:Cholagogues and Choleretics; D006888:Hydroxycholesterols; D011994:Recombinant Proteins; C099828:cholest-5-ene-3,4-diol; D002220:Carbamazepine; D010672:Phenytoin; D014580:Ursodeoxycholic Acid; D003577:Cytochrome P-450 Enzyme System; D002784:Cholesterol; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D010634:Phenobarbital