Metabolism of 4β-hydroxycholesterol in Humans

One of the major oxysterols in the human circulation is 4beta-hydroxycholesterol formed from cholesterol by the drug-metabolizing enzyme cytochrome P450 3A4. Deuterium-labeled 4beta-hydroxycholesterol was injected into two healthy volunteers, and the apparent half-life was found to be 64 and 60 h, respectively. We have determined earlier the half-lives for 7alpha-, 27-, and 24-hydroxycholesterol to be similar to0.5, 0.75, and 14 h, respectively. Patients treated with certain antiepileptic drugs have up to 20-fold increased plasma concentrations of 4beta-hydroxycholesterol. The apparent half-life of deuteriumlabeled 4beta-hydroxycholesterol in such a patient was found to be 52 h, suggesting that the high plasma concentration was because of increased synthesis rather than impaired clearance. 4beta-Hydroxycholesterol was converted into acidic products at a much slower rate than 7alpha-hydroxycholesterol in primary human hepatocytes, and 4beta-hydroxycholesterol was 7alpha-hydroxylated at a slower rate than cholesterol by recombinant human CYP7A1. CYP7B1 and CYP39A1 had no activity toward 4beta-hydroxycholesterol. These results suggest that the high plasma concentration of 4beta-hydroxycholesterol is because of its exceptionally slow elimination, probably in part because of the low rate of 7alpha-hydroxylation of the steroid. The findings are discussed in relation to a potential role of 4beta-hydroxycholesterol as a ligand for the nuclear receptor LXR.