Was 4β‐hydroxycholesterol ever going to be a useful marker of CYP3A4 activity?

Two papers in the November issue of the BJCP considered the use of 4β‐hydroxycholesterol (4βOHC) as an endogenous marker of the level of http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1337 activity, one with respect to the dosage of quetiapine and the other with reference to the dosage of tacrolimus. Both of these compounds are metabolized mainly by CYP3A4. Gjestad et al. 1 show a statistically significant correlation between the plasma concentration of 4βOHC and the steady‐state plasma concentration of quetiapine in psychiatric patients. However, a coefficient of determination (r ²) of about 0.3 hardly justifies the conclusion of close and useful correlation. Vanhove et al. 2 report that 4βOHC does not predict tacrolimus exposure or dose requirements during the first days after kidney transplantation. Even without performing these studies, it might have been predicted that 4βOHC is not likely to be a robust quantitative marker of either the absolute activity of CYP3A4 or a change in its activity as a consequence of enzyme induction 3. Indeed, it has already been well established that there are poor correlations between plasma 4βOHC and its ratio with cholesterol and the clearance of midazolam, the prototypic marker of CYP3A 4.

While 4βOHC is believed to be formed exclusively from cholesterol in both liver and gut by CYP3A4 with a minor contribution from CYP3A5, it is further metabolized mainly by CYP7A1 and CYP27A1 in the liver and gut 5, 6. Although the exact quantitative contribution of these CYPs to the net elimination of 4βOHC has not been established, the plasma level of 4βOHC and its ratio with cholesterol are dependent on all of these enzymes. The issue is complicated further by the co‐regulation of the four enzymes by the pregnane X receptor (http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=606) 7. PXR‐mediated induction of CYP3A4 by rifampicin appears to be accompanied not only by an increase in the plasma concentration of 4βOHC, as expected, but also possibly by an increase in its already long terminal half‐life 3, 5. Although the basal terminal half‐life of 4βOHC was not measured by Diczfalusy et al. 3 and a prolongation is inferred from a previous estimate which may not have captured the true terminal phase 5, a prolongation with co‐administration of rifampicin would be consistent with a report indicating that rifampicin decreases the mRNA expression of CYP7A1 in human hepatocytes 7. On the other hand, simultaneous induction of CYP7A1 would dampen the impact on 4βOHC levels of CYP3A4 induction. A further factor to be considered is that, as a PXR agonist, rifampicin inhibits the hepatic cholesterol ATP‐binding cassette efflux transporter A1 (http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=756) 8 and induces it in intestinal cells 6. A decrease in hepatic efflux of cholesterol would augment the effect of CYP3A4 induction on plasma 4βOHC concentration.

When proposing a biomarker, we suggest that due consideration be given to its specificity with respect to the elements involved in both the formation and clearance of the compound. This applies to the use of both plasma concentrations and metabolic ratios 9.

Nomenclature of targets and ligands

Key protein targets and ligands in this article are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY 10, and are permanently archived in the Concise Guide to PHARMACOLOGY 2017/18 11, 12, 13.

Competing Interests

There are no competing interests to declare.

Neuhoff, S. , and Tucker, G. T. (2018) Was 4β‐hydroxycholesterol ever going to be a useful marker of CYP3A4 activity?. Br J Clin Pharmacol, 84: 1620–1621. doi: 10.1111/bcp.13538.