title: 4β-Hydroxycholesterol, an endogenous marker of CYP3A4/5 activity in humans.
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.
authors.affiliation: Department of Laboratory Medicine, Division of Clinical Chemistry, Karolinska Institutet, Stockholm, Sweden. ulf.diczfalusy@karolinska.se
authors.forename: Ulf
authors.initials: U
authors.lastname: Diczfalusy
authors.forename: Hanna
authors.initials: H
authors.lastname: Nylén
authors.forename: Pontus
authors.initials: P
authors.lastname: Elander
authors.forename: Leif
authors.initials: L
authors.lastname: Bertilsson
mesh_terms: D015415:Biomarkers / Q000097:blood; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism*; D005006:Ethnicity / Q000235:genetics; D005838:Genotype; D006801:Humans; D006888:Hydroxycholesterols / Q000097:blood*; D010641:Phenotype; D012727:Sex Characteristics
chemical_list: D015415:Biomarkers; D006888:Hydroxycholesterols; C099828:cholest-5-ene-3,4-diol; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human