Impact of genetic and nongenetic factors on interindividual variability in 4β-hydroxycholesterol concentration

Abstract

These findings suggest that the CYP3A4*22, CYP3A5*3, and POR*28 variant alleles are of limited importance for overall individual variability in 4βOHC levels compared to nongenetic factors.

Use of 4β‐Hydroxycholesterol Plasma Concentrations as an Endogenous Biomarker of CYP3A Activity: Clinical Validation in Individuals With Type 2 Diabetes

“…A significant impact of CYP3A4*22 on the weightcorrected cholesterol-based metric was reported in a multivariate analysis performed in 147 renal transplant recipients receiving tacrolimus. 42 Our results are in agreement with a more extensive study (n = 655) recently published by Hole et al, 43 who reported no significant difference between levels of 4β-OHC in individuals expressing the CYP3A4*22 SNP and those wild type for CYP3A4. Due to its relatively low allele frequency (5-7% in Caucasians), it would be important and interesting to carry out larger sample size studies to evaluate the impact of CYP3A4*22 on cholesterol-based metrics.…”

Elevated 4β‐hydroxycholesterol/cholesterol ratio in anorexia nervosa patients

“…Genotyping of CYP3A4 and CYP3A5 would also have been of interest. Expression of the CYP3A5*1 allele has been associated with elevated 4βOHC levels, although a larger study did not find any association between 4βOHC levels and CYP3A5*3 or CYP3A4*22 polymorphisms . Other potential sources of inter‐individual variation in 4βOHC levels are ethnicity and inflammation …”

“…Cytochrome P450 (CYP) 3A enzymes play a major role in the metabolism of about 30% of clinically used drugs . Substantial inter‐individual variability in CYP3A activity exists due to a combination of genetic, environmental, and endogenous factors . CYP3A phenotype can be measured by the endogenous biomarker 4β‐hydroxycholesterol (4βOHC), which is metabolized from cholesterol by CYP3A4 and CYP3A5, the two most important CYP3A enzymes in humans .…”

4β‐Hydroxycholesterol level significantly correlates with steady‐state serum concentration of the CYP3A4 substrate quetiapine in psychiatric patients

“…The individual variability in CYP3A4 phenotype is extensive, as reflected by the more than 10‐fold interindividual variability in clearance of midazolam , the golden standard CYP3A4 probe agent. Genetic polymorphisms seem to play a secondary role for CYP3A4 phenotype variability , in contrast to several other CYP enzymes. Thus, the potential for individualized dosing based on genotyping of drugs primarily metabolized by CYP3A4 is limited.…”

“…Several studies have shown that 4βOHC levels change significantly following administration of both CYP3A4 inducers and inhibitors . Change in 4βOHC level seems to be more sensitive towards CYP3A4 induction than inhibition, which possibly reflects its long elimination half‐life .…”