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The major cholesterol oxidation products in the human circulation are 27-hydroxycholesterol, 24-hydroxycholesterol, and 7␣-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␣-and 24-hydroxycholesterol is 4␤-hydroxycholesterol. We now report that patients treated with the antiepileptic drugs phenobarbital, carbamazepine, or phenytoin have highly elevated levels of plasma 4␤-hydroxycholesterol. When patients with uncomplicated cholesterol gallstone disease were treated with ursodeoxycholic acid, plasma 4␤-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␤-hydroxycholesterol, whereas no conversion was observed with CYP1A2, CYP2C9, or CYP2B6. The concentration of 4␣-hydroxycholesterol in plasma was lower than the concentration of 4␤-hydroxycholesterol and not affected by treatment with the antiepileptic drugs or ursodeoxycholic acid. Together, these data suggest that 4␤-hydroxycholesterol in human circulation is formed by a cytochrome P450 enzyme.Cholesterol oxidation products (oxysterols) have recently attracted great interest because of their numerous biological actions. They have been implicated in bile acid biosynthesis, cholesterol transport, and gene regulation (1). In addition, many oxysterols are toxic to cells and induce apoptosis (2-4). These compounds can be formed either by cholesterol autooxidation or by the action of cholesterol-metabolizing enzymes. Several oxysterols can be formed by both mechanisms, i.e. 7␣-hydroxycholesterol. This oxysterol is a predominant cholesterol auto-oxidation product but is also formed by the hepatic enzyme cholesterol 7␣-hydroxylase. Major oxysterols in the human circulation include 27-hydroxycholesterol, 24-hydroxycholesterol, and 7␣-hydroxycholesterol (5). One additional oxysterol present in human plasma at a relatively high concentration is 4␤-hydroxycholesterol (6). Very little is known about its formation or metabolism. We have shown earlier that small amounts of this oxysterol are formed, together with 4␣-hydroxycholesterol, during in vitro oxidation of low density lipoprotein, and low levels of the two oxysterols were also found in human atherosclerotic plaques (7). The ratio between 4␣-and 4␤-hydroxycholesterol was close to one both in oxidized LDL 1 and in plaques, and the amount formed in oxidized LDL was only a small percent of the dominating oxysterol, 7-oxocholesterol. These data suggested that very little 4␤-hydroxycholesterol is formed by cholesterol auto-oxidation. Because relatively high levels were reported in human plasma we hypothesized that this compound is formed in vivo by an enzymatic reaction. 4␣-and 4␤-hydroxycholesterol were determined in plasma from volunteers and patients, and it was found that patients treated with certain antiepileptic drugs, known...

Primary sclerosing cholangitis (PSC) is a biliary destructive disease mostly affecting patients with ulcerative colitis (UC). PSC has been suggested to be an independent risk factor for the development of colorectal malignancy in UC. Patients with PSC also have an increased risk of developing cholangiocarcinoma. This study aimed at assessing the cumulative risk of colorectal neoplasia in PSC and UC, and also to determine risk factors for the development of cholangiocarcinoma. Fifty-eight PSC patients were included. Forty PSC patients having extensive UC were each matched to two control patients of the same age, with extensive colitis and a comparable duration of the colitis, but without PSC. All UC patients had been under colonoscopic surveillance with multiple biopsies. Among the 40 PSC patients with UC, 16 developed colonic dysplasia or carcinoma, versus 10 in the control group (P < .001). The absolute cumulative risk of developing colorectal dysplasia/carcinoma in the PSC/UC groups was 9%, 31%, and 50% after 10, 20, and 25 years of disease duration. In the group with UC only, the corresponding risk was 2%, 5%, and 10%, respectively (P < .001). Ten patients with PSC developed cholangiocarcinoma, all but one having UC. In the control group, no cholangiocarcinoma occurred. Patients with PSC and UC with colorectal neoplasia developed cholangiocarcinoma significantly more often compared with patients with UC and PSC without colonic dysplasia/carcinoma (P < .02). This study demonstrates not only that patients with PSC and UC have a significantly higher risk of developing colorectal neoplasia compared with patients having UC only, but also that patients with PSC and UC having colorectal neoplasia are more prone to develop cholangiocarcinoma.

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