Baker Elizabeth, Harris William T, Guimbellot Jennifer S, Bliton Kyle, Rowe Steven M, Raju S Vamsee, Oates Gabriela R
Medicine University of Alabama at Birmingham 1808 7th Ave S, BDB 853 Birmingham, AL 35233 United States.
Medicine University of Alabama at Birmingham 1808 7th Ave S, BDB 853 Birmingham, AL 35233 United States; The University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
J Cyst Fibros. 2024 Sep;23(5):959-966. doi: 10.1016/j.jcf.2024.07.010. Epub 2024 Jul 20.
Acrolein, an aldehyde in smoke from tobacco products, inhibits CFTR function in vitro. Ivacaftor is an FDA-approved potentiator that improves mutant CFTR function. This human clinical study investigated the relationship between two urinary markers of tobacco smoke exposure - the acrolein metabolite 3-HPMA and the nicotine metabolite NNAL - and sweat chloride response to ivacaftor in the G551D Observational Trial (GOAL).
3-HPMA (low: <50th centile; moderate: 50-75th centile; high: >75th centile) and NNAL (detectable/undetectable) in GOAL samples was quantified with LC-MS/MS. Self-report of tobacco smoke exposure (Y/N) served as a subjective measure. Change in sweat chloride from pre- to 6 months post-ivacaftor treatment (ΔSC) was the primary CFTR-dependent readout.
The sample included 151 individuals, mean age 20.7 (SD 11.4) years, range 6-59 years. Smoke exposure prevalence was 15 % per self-reports but 27 % based on detectable NNAL. 3-HPMA was increased in those reporting tobacco smoke exposure (607 vs 354 ng/ml, p = 0.008), with a higher proportion of smoke-exposed in the high- vs low-acrolein group (31 % vs 9 %, p=0.040). Compared to low-acrolein counterparts, high-acrolein participants experienced less decrease in sweat chloride (-35.2 vs -48.2 mmol/L; p = 0.020) and had higher sweat chloride values (50.6 vs 37.6 mmol/L; p = 0.020) 6 months post-ivacaftor. The odds of ivacaftor-mediated potentiation to near normative CFTR function (defined as SC <40 mmol/L) was more than twice as high in the low-acrolein cohort (OR: 2.51, p = 0.026).
Increased urinary 3-HPMA, an acrolein metabolite of tobacco smoke, is associated with a diminished sweat chloride response to ivacaftor potentiation of CFTR function.
丙烯醛是烟草制品烟雾中的一种醛类物质，在体外可抑制囊性纤维化跨膜传导调节因子（CFTR）的功能。依伐卡托是一种经美国食品药品监督管理局（FDA）批准的增强剂，可改善突变型CFTR的功能。这项人体临床研究在G551D观察性试验（GOAL）中，调查了烟草烟雾暴露的两种尿液标志物——丙烯醛代谢物3 - 羟基苯丙烯酸（3 - HPMA）和尼古丁代谢物可替宁（NNAL）——与依伐卡托治疗后汗液氯化物反应之间的关系。
采用液相色谱 - 串联质谱法（LC - MS/MS）对GOAL研究样本中的3 - HPMA（低：低于第50百分位数；中：第50 - 75百分位数；高：高于第75百分位数）和NNAL（可检测/不可检测）进行定量分析。烟草烟雾暴露的自我报告（是/否）作为一种主观测量方法。依伐卡托治疗前至治疗后6个月汗液氯化物的变化（ΔSC）是主要的CFTR依赖性指标。
样本包括151名个体，平均年龄20.7（标准差11.4）岁，年龄范围为6 - 59岁。根据自我报告，烟雾暴露患病率为15%，但基于可检测到的NNAL则为27%。报告有烟草烟雾暴露者的3 - HPMA水平升高（607 vs 354 ng/ml，p = 0.008），高丙烯醛组与低丙烯醛组相比，烟雾暴露比例更高（31% vs 9%，p = 0.040）。与低丙烯醛组相比，高丙烯醛组参与者在依伐卡托治疗6个月后汗液氯化物的下降幅度较小（-35.2 vs -48.2 mmol/L；p = 0.020），且汗液氯化物值更高（50.6 vs 37.6 mmol/L；p = 0.020）。在低丙烯醛队列中，依伐卡托介导的CFTR功能增强至接近正常水平（定义为汗液氯化物<40 mmol/L）的几率是高丙烯醛队列的两倍多（比值比：2.51，p = 0.026）。
尿液中3 - HPMA（一种烟草烟雾中的丙烯醛代谢物）水平升高，与依伐卡托增强CFTR功能后汗液氯化物反应减弱有关。
