Oda Ayako, Suzuki Yosuke, Sato Haruki, Koyama Teruhide, Nakatochi Masahiro, Momozawa Yukihide, Tanaka Ryota, Ono Hiroyuki, Tatsuta Ryosuke, Ando Tadasuke, Shin Toshitaka, Wakai Kenji, Matsuo Keitaro, Itoh Hiroki, Ohno Keiko
Department of Medication Use Analysis and Clinical Research, Meiji Pharmaceutical University, Kiyose, Tokyo, Japan.
Department of Epidemiology for Community Health and Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Clin Transl Sci. 2024 Mar;17(3):e13768. doi: 10.1111/cts.13768.
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 CYP3A51 carriers and 225 non-carriers. Twenty-six patients with chronic kidney disease (CKD) with CYP3A51 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 CYP3A51 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 CYP3A51 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.
血浆4β-羟基胆固醇（OHC）作为一种指示CYP3A活性的内源性底物已受到关注。血浆4β-OHC由CYP3A4和CYP3A5羟基化以及胆固醇自氧化产生。血浆4α-OHC由胆固醇自氧化产生，不受CYP3A活性影响。本研究旨在评估与血浆4β-OHC浓度和4β-OHC/总胆固醇（TC）比值相比，血浆4β-OHC浓度减去血浆4α-OHC浓度（4β-OHC-4α-OHC）在CYP3A活性横断面评估中的实用性。416名普通成年人被分为191名CYP3A51携带者和225名非携带者。26名携带CYP3A51等位基因的慢性肾脏病（CKD）患者被分为14名CKD 3期患者和12名4-5D期患者。评估了这三个指标的受试者工作特征曲线下面积（AUC），以预测普通成年人中CYP3A51等位基因的有无，以及预测CKD患者的CKD 3期或4-5D期。在普通成年人和CKD患者中，4β-OHC-4α-OHC的AUC与血浆4β-OHC浓度的AUC之间无显著差异。在普通成年人中，4β-OHC-4α-OHC的AUC显著小于4β-OHC/TC比值的AUC（p = 0.025），但在CKD患者中这两个指标无差异。总之，在本对普通成年人及携带CYP3A51等位基因的CKD患者的CYP3A活性横断面评估中，4β-OHC-4α-OHC的实用性与血浆4β-OHC浓度或4β-OHC/TC比值无异。然而，由于本研究的研究设计和受试者选择存在局限性，这些发现需要在进一步研究中进行验证。
