Evaluation of the usefulness of plasma 4β-hydroxycholesterol concentration normalized by 4α-hydroxycholesterol for accurate CYP3A phenotyping

Abstract

Plasma 4β-hydroxycholesterol (OHC) has drawn attention as an endogenous substrate indicating CYP3A activity. Plasma 4β-OHC is produced by hydroxylation by CYP3A4 and CYP3A5 and by cholesterol autoxidation. Plasma 4α-OHC is produced by cholesterol autoxidation and not affected by CYP3A activity. This study aimed to evaluate the usefulness of plasma 4β-OHC concentration minus plasma 4α-OHC concentration (4β-OHC-4α-OHC) compared with plasma 4β-OHC concentration and 4β-OHC/total cholesterol (TC) ratio in cross-sectional evaluation of CYP3A activity. Four hundred sixteen general adults were divided into 191 CYP3A5*1 carriers and 225 non-carriers. Twenty-six patients with chronic kidney disease (CKD) with CYP3A5*1 allele were divided into 14 with CKD stage 3 and 12 with stage 4-5D. Area under the receiver operating characteristic curve (AUC) for the three indices were evaluated for predicting presence or absence of CYP3A5*1 allele in general adults, and for predicting CKD stage 3 or stage 4-5D in patients with CKD. There was no significant difference between AUC of 4β-OHC-4α-OHC and AUC of plasma 4β-OHC concentration in general adults and in patients with CKD. AUC of 4β-OHC-4α-OHC was significantly smaller than that of 4β-OHC/TC ratio in general adults (p = 0.025), but the two indices did not differ in patients with CKD. In conclusion, in the present cross-sectional evaluation of CYP3A activity in general adults and in patients with CKD with CYP3A5*1 allele, the usefulness of 4β-OHC-4α-OHC was not different from plasma 4β-OHC concentration or 4β-OHC/TC ratio. However, because of the limitations in study design and subject selection of this research, these findings require verification in further studies.

FIGURE 1

Comparison of (a) plasma 4β‐OHC concentration (ng/mL), (b) 4β‐OHC/TC ratio, (c) 4β‐OHC–4α‐OHC (ng/mL), and (d) plasma 4α‐OHC concentration (ng/mL) between CYP3A5*1 carriers and non‐carriers in general adults. Data normality was analyzed by Shapiro–Wilk test, and all parameters were analyzed by Mann–Whitney U test. The horizontal line represents the median. 4α‐OHC, 4α‐hydroxycholesterol; 4β‐OHC, 4β‐hydroxycholesterol; CYP, cytochrome P450; TC, total cholesterol.

FIGURE 2

Comparison of (a) plasma 4β‐OHC concentration (ng/mL), (b) 4β‐OHC/TC ratio, (c) 4β‐OHC–4α‐OHC (ng/mL), (d) plasma 4α‐OHC concentration (ng/mL) between CKD stage 3 and stage 4–5D in patients with CKD with CYP3A5*1 allele. Data normality was analyzed by Shapiro–Wilk test. Plasma 4α‐OHC concentration (ng/mL) was analyzed by Mann–Whitney U test, and the horizontal line represents the median. The other parameters were analyzed by Welch's t‐test, and the horizontal line represents the mean. 4α‐OHC, 4α‐hydroxycholesterol; 4β‐OHC, 4β‐hydroxycholesterol; CKD, chronic kidney disease; TC, total cholesterol.

FIGURE 3

Receiver operating characteristic curves of CYP3A activity indices for predicting presence or absence of CYP3A5*1 allele in general adults. 4α‐OHC, 4α‐hydroxycholesterol; 4β‐OHC, 4β‐hydroxycholesterol; TC, total cholesterol.

FIGURE 4

Receiver operating characteristic curves of CYP3A activity indices for predicting CKD stage 3 or stage 4–5D in patients with CKD with CYP3A5*1 allele. 4α‐OHC, 4α‐hydroxycholesterol; 4β‐OHC, 4β‐hydroxycholesterol; CKD, chronic kidney disease; TC, total cholesterol.