4β-Hydroxycholesterol, an endogenous marker of CYP3A4/5 activity in humans

Br J Clin Pharmacol. 2011 Feb;71(2):183-9. doi: 10.1111/j.1365-2125.2010.03773.x.

Abstract

We have proposed that 4β-hydroxycholesterol (4β-OHC) may be used as an endogenous marker of CYP3A activity. The cholesterol metabolite 4β-OHC is formed by CYP3A4. Treatment of patients with strong inducers of CYP3A enzymes, e.g. anti-epileptic drugs, resulted in 10-fold increased concentrations of plasma 4β-OHC, while treatment with CYP3A inhibitors such as ritonavir or itraconazole resulted in decreased plasma concentrations. There was a relationship between the 4β-OHC concentration and the number of active CYP3A5*1 alleles showing that 4β-OHC was not only formed by CYP3A4, but also by CYP3A5. The concentration of 4β-OHC was higher in women than in men, confirming previous studies indicating a gender difference in CYP3A4/5-activity. The rate of elimination of 4β-OHC is slow (half-life 17 days) which results in stable plasma concentrations within individuals, but limits its use to study rapid changes in CYP3A activity. In short-term studies exogenous markers such as midazolam or quinine may be superior, but in long-term studies 4β-OHC is a sensitive marker of CYP3A activity, especially to assess induction but also inhibition. Under conditions where the cholesterol concentration is changing, the ratio of 4β-OHC:cholesterol may be used as an alternative to 4β-OHC itself. The use of an endogenous CYP3A marker has obvious advantages and may be of value both during drug development and for monitoring CYP3A activity in patients.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Biomarkers / blood
  • Cytochrome P-450 CYP3A / genetics
  • Cytochrome P-450 CYP3A / metabolism*
  • Ethnic Groups / genetics
  • Genotype
  • Humans
  • Hydroxycholesterols / blood*
  • Phenotype
  • Sex Characteristics

Substances

  • Biomarkers
  • Hydroxycholesterols
  • cholest-5-ene-3,4-diol
  • CYP3A5 protein, human
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human