Department of Clinical Pharmacology, University of Helsinki, Helsinki, Finland.
Basic Clin Pharmacol Toxicol. 2012 Mar;110(3):245-52. doi: 10.1111/j.1742-7843.2011.00792.x. Epub 2011 Oct 7.
Cholesterol 7α-hydroxylase (CYP7A1) is the rate-limiting enzyme of bile acid production in human beings, and organic anion-transporting polypeptide 1B1 (OATP1B1) may influence bile acid hepatic uptake and cholesterol and bile acid synthesis rate. Our purpose was to investigate the effects of gender and CYP7A1 and SLCO1B1 polymorphisms on the fasting plasma concentrations of bile acids, bile acid synthesis marker and total cholesterol in a Finnish population. Fasting plasma concentrations of 16 endogenous bile acids, their synthesis marker (7α-hydroxy-4-cholesten-3-one) and total cholesterol were measured in 243 samples from 143 healthy volunteers. The volunteers were genotyped for 6 haplotype-tagging single-nucleotide polymorphisms (SNPs) of CYP7A1 and two functionally relevant SNPs in SLCO1B1. The mean plasma concentrations of chenodeoxycholic acid, glycochenodeoxycholic acid, ursodeoxycholic acid and glycoursodeoxycholic acid were 61-111% higher in men than in women (P ≤ 0.001). Accordingly, the mean concentration of total bile acids was 51% higher in men than in women (P = 0.001). The CYP7A1 rs8192879 and rs1023652 SNPs were associated with deoxycholic acid and hyodeoxycholic acid concentrations, respectively, but the associations were not significant after correction for multiple testing. None of the six CYP7A1 SNPs was associated with the plasma concentrations of cholesterol or 7α-hydroxy-4-cholesten-3-one. SLCO1B1 genotype was associated with total plasma cholesterol concentration only, but the association was not significant after correction for multiple testing. In general, the gender contributes substantially more to variation in fasting plasma bile acid concentrations than CYP7A1 or SLCO1B1 polymorphism do. Common genetic variability in CYP7A1 is unlikely to play a significant role in cholesterol metabolism and bile acid homeostasis under normal physiological conditions.
胆固醇 7α-羟化酶（CYP7A1）是人类胆汁酸生成的限速酶，有机阴离子转运多肽 1B1（OATP1B1）可能影响胆汁酸的肝摄取以及胆固醇和胆汁酸的合成速率。我们的目的是研究性别以及 CYP7A1 和 SLCO1B1 多态性对芬兰人群空腹血浆胆汁酸、胆汁酸合成标志物和总胆固醇浓度的影响。在 143 名健康志愿者的 243 个样本中，测量了 16 种内源性胆汁酸、其合成标志物（7α-羟基-4-胆甾烯-3-酮）和总胆固醇的空腹血浆浓度。志愿者对 CYP7A1 的 6 个单体型标签单核苷酸多态性（SNP）和 SLCO1B1 中的 2 个功能相关 SNP 进行了基因分型。男性的鹅脱氧胆酸、甘氨鹅脱氧胆酸、熊脱氧胆酸和甘氨熊脱氧胆酸的平均血浆浓度比女性高 61-111%（P ≤ 0.001）。因此，男性的总胆汁酸平均浓度比女性高 51%（P = 0.001）。CYP7A1 rs8192879 和 rs1023652 SNP 分别与脱氧胆酸和去氧鹅脱氧胆酸浓度相关，但在进行多次检验校正后，关联并不显著。CYP7A1 的 6 个 SNP 均与胆固醇或 7α-羟基-4-胆甾烯-3-酮的血浆浓度无关。SLCO1B1 基因型仅与总血浆胆固醇浓度相关，但在进行多次检验校正后，关联并不显著。总的来说，与 CYP7A1 或 SLCO1B1 多态性相比，性别对空腹血浆胆汁酸浓度的变异性贡献更大。在正常生理条件下，CYP7A1 常见的遗传多态性不太可能在胆固醇代谢和胆汁酸稳态中发挥重要作用。
