Antiepileptic drugs increase plasma levels of 4β-hydroxycholesterol in humans -: Evidence for involvement of cytochrome P450 3A4

The major cholesterol oxidation products in the human circulation are 27-hydroxycholesterol, 24-hydroxy-cholesterol, and 7 alpha -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 7 alpha- and 24-hydroxycholesterol is 4 beta -hydroxycholesterol. We now report that patients treated with the antiepileptic drugs phenobarbital, carbamazepine, or phenytoin have highly elevated levels of plasma 4 beta -hydroxycholesterol. When patients with uncomplicated cholesterol gallstone disease were treated with ursodeoxycholic acid, plasma 4 beta -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 4 beta -hydroxycholesterol, whereas no conversion was observed with CYP1A2, CYP2C9, or CYP2B6. The concentration of 4 alpha -hydroxycholesterol in plasma was lower than the concentration of 4 beta -hydroxycholesterol and not affected by treatment with the antiepileptic drugs or ursodeoxycholic acid. Together, these data suggest that 4 beta -hydroxycholesterol in human circulation is formed by a cytochrome P450 enzyme.