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: K Bodin, L Bretillon, Y Aden, L Bertilsson, U Broomé, C Einarsson, U Diczfalusy
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 276 Issue 42 Pg. 38685-9 (Oct 19 2001) ISSN: 0021-9258 [Print] United States
• PMID: 11514559 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anticonvulsants
• Cholagogues and Choleretics
• Hydroxycholesterols
• Recombinant Proteins
• cholest-5-ene-3,4-diol
• Carbamazepine
• Phenytoin
• Ursodeoxycholic Acid
• Cytochrome P-450 Enzyme System
• Cholesterol
• Mixed Function Oxygenases
• CYP3A protein, human
• Cytochrome P-450 CYP3A
• CYP3A4 protein, human
• Phenobarbital

Topics

• Adult
• Aged
• Animals
• Anticonvulsants (pharmacology)
• Carbamazepine (pharmacology)
• Cell Line
• Cholagogues and Choleretics (pharmacology)
• Cholesterol (metabolism)
• Cytochrome P-450 CYP3A
• Cytochrome P-450 Enzyme System (metabolism)
• Dose-Response Relationship, Drug
• Female
• Humans
• Hydroxycholesterols (blood)
• Insecta
• Kinetics
• Male
• Microsomes (metabolism)
• Middle Aged
• Mixed Function Oxygenases (metabolism)
• Phenobarbital (pharmacology)
• Phenytoin (pharmacology)
• Recombinant Proteins (metabolism)
• Ursodeoxycholic Acid (pharmacology)