Antiepileptic drugs increase plasma levels of 4beta-hydroxycholesterol in humans: evidence for involvement of cytochrome p450 3A4
| Autor: | K, Bodin, L, Bretillon, Y, Aden, L, Bertilsson, U, Broomé, C, Einarsson, U, Diczfalusy |
|---|---|
| Rok vydání: | 2001 |
| Předmět: |
Adult
Male Cholagogues and Choleretics Insecta Dose-Response Relationship Drug Ursodeoxycholic Acid Middle Aged Hydroxycholesterols Recombinant Proteins Cell Line Mixed Function Oxygenases Kinetics Carbamazepine Cholesterol Cytochrome P-450 Enzyme System Microsomes Phenobarbital Phenytoin Animals Cytochrome P-450 CYP3A Humans Anticonvulsants Female Aged |
| Zdroj: | The Journal of biological chemistry. 276(42) |
| ISSN: | 0021-9258 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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