Studies on 4b-hydroxycholesterol, a marker of CYP3A activity, and its association with 25-hydroxyvitamin D
Author: Nylén, Hanna
Date: 2015-12-17
Location: Föreläsningssal 4Z, plan 4, Alfred Nobels allé 8, Karolinska Institutet, Huddinge
Time: 10.00
Department: Inst för laboratoriemedicin / Dept of Laboratory Medicine
Abstract
Cholesterol is a vital compound that can undergo cytochrome P450 (CYP) mediated
conversion into steroid hormones, bile acids and oxysterols. CYP enzymes are present in all
human tissues and mediate the metabolism of several endogenous and exogenous compounds
such as steroids and drugs. Vitamin D status has been shown to be important for several
biological processes such as drug metabolism, modulation of the immune system and bone
health. Enzymes in subfamily CYP3A (CYP3A4, CYP3A5, CYP3A7 and CYP3A43) are
present in liver and intestine. They metabolize about 50% of all prescribed drugs. Genetic
factors, age, sex, ethnicity and environmental factors influence the activity and expression of
CYP3A enzymes. These factors combined cause wide inter-patient variability in CYP3A
mediated drug response. There are a number of clinical markers to assess the CYP3A
activity, e.g. plasma midazolam clearance, quinine metabolic ratio and 4β-
hydroxycholesterol/cholesterol ratio.
In the present study the plasma levels of 4β- hydroxycholesterol and the 4β-hydroxycholesterol/cholesterol ratio has been evaluated as markers of CYP3A activity during enzyme induction by a number of drugs (carbamazepine in Papers I and III, rifampicin in Papers IV-V and efavirenz in Paper V) and by pregnancy (Paper III). The association between CYP3A activity and vitamin D status has also been studied (Paper IV-V). In Paper I, carbamazepine treatment in children with epilepsy doubled the plasma levels of 4β-hydroxycholesterol within two weeks of treatment. The increase was 5 to 10-fold within eight weeks treatment. In Paper III, pregnancy increased the 4β- hydroxycholesterol/cholesterol ratio and the plasma levels of cholesterol. Newborn children had the same CYP3A activity as adults as indicated by similar 4β-hydroxycholesterol/ cholesterol ratios. Carbamazepine treatment during pregnancy further increased the CYP3A activity in one mother and her child. In Papers IV-V, rifampicin-mediated CYP3A induction did not affect the plasma levels of 25-hydroxyvitamin D in healthy volunteers or in tuberculosis-HIV co-infected patients. In tuberculosis-HIV co-infected patients there was a significant negative correlation between the plasma levels of 25- hydroxyvitamin D and the 4β-hydroxycholesterol/cholesterol ratio already at initiation of treatment (Paper V). Efavirenz treatment caused a transient decrease in the plasma levels of 25-hydroxyvitamin D in HIV-infected patients (Paper V).
To summarize, 4β-hydroxycholesterol and the 4β-hydroxycholesterol/cholesterol ratio are useful as markers of CYP3A induction. 4β-Hydroxycholesterol is a non-invasive endogenous clinical marker that is easy to use also in children and vulnerable patient groups. The blood samples can be taken at any time of the day regardless of food intake.
In the present study the plasma levels of 4β- hydroxycholesterol and the 4β-hydroxycholesterol/cholesterol ratio has been evaluated as markers of CYP3A activity during enzyme induction by a number of drugs (carbamazepine in Papers I and III, rifampicin in Papers IV-V and efavirenz in Paper V) and by pregnancy (Paper III). The association between CYP3A activity and vitamin D status has also been studied (Paper IV-V). In Paper I, carbamazepine treatment in children with epilepsy doubled the plasma levels of 4β-hydroxycholesterol within two weeks of treatment. The increase was 5 to 10-fold within eight weeks treatment. In Paper III, pregnancy increased the 4β- hydroxycholesterol/cholesterol ratio and the plasma levels of cholesterol. Newborn children had the same CYP3A activity as adults as indicated by similar 4β-hydroxycholesterol/ cholesterol ratios. Carbamazepine treatment during pregnancy further increased the CYP3A activity in one mother and her child. In Papers IV-V, rifampicin-mediated CYP3A induction did not affect the plasma levels of 25-hydroxyvitamin D in healthy volunteers or in tuberculosis-HIV co-infected patients. In tuberculosis-HIV co-infected patients there was a significant negative correlation between the plasma levels of 25- hydroxyvitamin D and the 4β-hydroxycholesterol/cholesterol ratio already at initiation of treatment (Paper V). Efavirenz treatment caused a transient decrease in the plasma levels of 25-hydroxyvitamin D in HIV-infected patients (Paper V).
To summarize, 4β-hydroxycholesterol and the 4β-hydroxycholesterol/cholesterol ratio are useful as markers of CYP3A induction. 4β-Hydroxycholesterol is a non-invasive endogenous clinical marker that is easy to use also in children and vulnerable patient groups. The blood samples can be taken at any time of the day regardless of food intake.
List of papers:
I. Wide K, Larsson H, Bertilsson L, Diczfalusy U. Time course of the increase in 4β-hydroxycholesterol concentration during carbamazepine treatment of paediatric patients with epilepsy. Br J Clin Pharmacol. 65, 708-715 (2008).
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Diczfalusy U, Nylén H, Elander P, Bertilsson L. 4β-Hydroxycholesterol, an endogenous marker of CYP3A4/5 activity in humans. Br J Clin Pharmacol. 71, 183-189 (2011).
Fulltext (DOI)
Pubmed
View record in Web of Science®
III. Nylén H, Sergel S, Forsberg L, Lindemalm S, Bertilsson L, Wide K, Diczfalusy U. Cytochrome P450 3A activity in mothers and their neonates as determined by plasma 4β-hydroxycholesterol. Eur J Clin Pharmacol. 67(7), 715-722 (2011).
Fulltext (DOI)
Pubmed
View record in Web of Science®
IV. Nylén H, Björkhem-Bergman L, Ekström L, Roh HK, Bertilsson L, Eliasson E, Lindh JD, Diczfalusy U. Plasma levels of 25-hydroxyvitamin D3 and in vivo markers of Cytochrome P450 3A activity in Swedes and Koreans. Effects of a genetic polymorphism and oral contraceptives. Basic Clin Pharmacol Toxicol. 115(4), 366-371 (2014).
Fulltext (DOI)
Pubmed
View record in Web of Science®
V. Nylén H, Habtewold A, Makonnen E, Amogne W, Yimer G, Aderaye G, Bertilsson L, Burhenne J, Diczfalusy U, Aklillu E. Effect of efavirenz-based ART and rifampicin-based anti-tuberculosis cotreatment on Vitamin D status. [Manuscript]
I. Wide K, Larsson H, Bertilsson L, Diczfalusy U. Time course of the increase in 4β-hydroxycholesterol concentration during carbamazepine treatment of paediatric patients with epilepsy. Br J Clin Pharmacol. 65, 708-715 (2008).
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Diczfalusy U, Nylén H, Elander P, Bertilsson L. 4β-Hydroxycholesterol, an endogenous marker of CYP3A4/5 activity in humans. Br J Clin Pharmacol. 71, 183-189 (2011).
Fulltext (DOI)
Pubmed
View record in Web of Science®
III. Nylén H, Sergel S, Forsberg L, Lindemalm S, Bertilsson L, Wide K, Diczfalusy U. Cytochrome P450 3A activity in mothers and their neonates as determined by plasma 4β-hydroxycholesterol. Eur J Clin Pharmacol. 67(7), 715-722 (2011).
Fulltext (DOI)
Pubmed
View record in Web of Science®
IV. Nylén H, Björkhem-Bergman L, Ekström L, Roh HK, Bertilsson L, Eliasson E, Lindh JD, Diczfalusy U. Plasma levels of 25-hydroxyvitamin D3 and in vivo markers of Cytochrome P450 3A activity in Swedes and Koreans. Effects of a genetic polymorphism and oral contraceptives. Basic Clin Pharmacol Toxicol. 115(4), 366-371 (2014).
Fulltext (DOI)
Pubmed
View record in Web of Science®
V. Nylén H, Habtewold A, Makonnen E, Amogne W, Yimer G, Aderaye G, Bertilsson L, Burhenne J, Diczfalusy U, Aklillu E. Effect of efavirenz-based ART and rifampicin-based anti-tuberculosis cotreatment on Vitamin D status. [Manuscript]
Institution: Karolinska Institutet
Supervisor: Diczfalusy, Ulf
Issue date: 2015-11-26
Rights:
Publication year: 2015
ISBN: 978-91-7676-097-0
Statistics
Total Visits
Views | |
---|---|
Studies ...(legacy) | 391 |
Studies ... | 155 |
Total Visits Per Month
October 2023 | November 2023 | December 2023 | January 2024 | February 2024 | March 2024 | April 2024 | |
---|---|---|---|---|---|---|---|
Studies ... | 3 | 0 | 0 | 1 | 0 | 1 | 0 |
File Visits
Views | |
---|---|
Thesis_Hanna_Nylen.pdf | 624 |
Thesis_Hanna_Nylen.pdf(legacy) | 372 |
Spikblad_Hanna_Nylen.pdf(legacy) | 48 |
Spikblad_Hanna_Nylen.pdf | 27 |
null(legacy) | 1 |
null(legacy) | 1 |
Top country views
Views | |
---|---|
United States | 112 |
Sweden | 101 |
Germany | 47 |
South Korea | 36 |
China | 23 |
Japan | 18 |
Poland | 16 |
Ireland | 8 |
Finland | 7 |
Brazil | 5 |
Top cities views
Views | |
---|---|
Ashburn | 45 |
Seoul | 31 |
Kiez | 20 |
Woodbridge | 13 |
Wilmington | 12 |
Öckerö | 9 |
Kraków | 8 |
Beijing | 7 |
Henryk | 7 |
Dublin | 6 |