Factors Influencing Plasma Coproporphyrin-I Concentration as Biomarker of OATP1B Activity in Patients With Rheumatoid Arthritis
Factors Influencing Plasma Coproporphyrin-I Concentration as Biomarker of OATP1B Activity in Patients With Rheumatoid Arthritis
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DOI：
10.1002/cpt.2375
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发表时间：
2021-08-10
影响因子：
6.7
通讯作者：
Itoh, Hiroki
中科院分区：
文献类型：
--
作者：
Ono, Hiroyuki;Tanaka, Ryota;Itoh, Hiroki
有机阴离子转运多肽（oats） 1B是主要表达于窦膜的药物转运体。在以往的报道中，遗传因素、尿毒症毒素之一的3-羧基-4-甲基-5-丙基-2-呋喃丙酸（CMPF）、炎性细胞因子如肿瘤坏死因子- α (tnf - α)和白细胞介素-6 （IL-6）在体外降低OATP1B1活性，但这些因素在体内的作用尚未阐明。血浆co - proporphyrin- i （CP-I）被认为是OATP1B高度精确的内源性底物。本研究以类风湿关节炎（RA）患者为研究对象，利用血浆cp - 1浓度评估基因多态性、尿毒症毒素和炎症因子等因素对OATP1B活性的影响。37例满足选择标准的RA门诊患者在招募时（基线）和下次就诊时进行分析。OATP1B1*15携带者的cp - 1浓度往往高于非携带者。血浆cp - 1与CMPF浓度呈正相关，但与IL-6或tnf - α浓度无关。通过逐步选择进行多元logistic回归分析，发现血浆CMPF浓度和OATP1B1*15等位基因分别是影响基线和下次访视时血浆cp - 1浓度的独立显著因素。总之，目前的结果表明，炎症因子对OATP1B活性没有临床显著影响，而遗传多态性和尿毒症毒素的影响应该被考虑在内。
Organic anion transporting polypeptides (OATPs) 1B are drug transporters mainly expressed in the sinusoidal membrane. In previous reports, genetic factor, 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF), which is one of the uremic toxins, inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) decreased OATP1B1 activity in vitro, but in vivo effects of these factors have not been elucidated. Plasma coproporphyrin-I (CP-I) is spotlighted as a highly accurate endogenous substrate of OATP1B. This study focused on patients with rheumatoid arthritis (RA) and evaluated the influence of several factors comprising gene polymorphisms, uremic toxins, and inflammatory cytokines on OATP1B activity using plasma CP-I concentration. Thirty-seven outpatients with RA who satisfied the selection criteria were analyzed at the time of recruitment (baseline) and at the next visit. OATP1B1*15 carriers tended to have higher CP-I concentration compared with noncarriers. Plasma CP-I correlated positively with CMPF concentration, but did not correlate with IL-6 or TNF-alpha concentration. Multiple logistic regression analysis by stepwise selection identified plasma CMPF concentration and OATP1B1*15 allele as significant factors independently affecting plasma CP-I concentration at baseline and at the next visit, respectively. In conclusion, the present results suggest that inflammatory cytokines do not have clinically significant effects on OATP1B activity, whereas the effects of genetic polymorphisms and uremic toxins should be considered.