Genaro-Mattos Thiago C, Klingelsmith Korinne B, Allen Luke B, Anderson Allison, Tallman Keri A, Porter Ned A, Korade Zeljka, Mirnics Károly
Munroe-Meyer Institute for Genetics and Rehabilitation, University of Nebraska Medical Center, Omaha, Nebraska 68105, United States.
Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska 68198, United States.
ACS Pharmacol Transl Sci. 2021 Feb 17;4(2):848-857. doi: 10.1021/acsptsci.1c00012. eCollection 2021 Apr 9.
Sterol biosynthesis is a critical homeostatic mechanism of the body. Sterol biosynthesis begins during early embryonic life and continues throughout life. Many commonly used medications, prescribed >200 million times in the United States annually, have a sterol biosynthesis inhibition side effect. Using our high-throughput LC-MS/MS method, we assessed the levels of post-lanosterol sterol intermediates (lanosterol, desmosterol, and 7-dehydrocholesterol (7-DHC)) and cholesterol in 1312 deidentified serum samples from pregnant women. 302 samples showing elevated 7-DHC were analyzed for the presence of 14 medications known to inhibit the 7-dehydrocholesterol reductase enzyme (DHCR7) and increase 7-DHC. Of the 302 samples showing 7-DHC elevation, 43 had detectable levels of prescription medications with a DHCR7-inhibiting side effect. Taking more than one 7-DHC-elevating medication in specific combinations (polypharmacy) might exacerbate the effect on 7-DHC levels in pregnant women, suggesting a potentially additive or synergistic effect. As 7-DHC and 7-DHC-derived oxysterols are toxic, and as DHCR7-inhibiting medications are considered teratogens, our findings raise potential concerns regarding the use of prescription medication with a DHCR7-inhibiting side effect during pregnancy. The use of prescription medications during pregnancy is sometimes unavoidable, but choosing a medication without a DHCR7-inhibiting side effect might lead to a heathier pregnancy and prevent putatively adverse outcomes for the developing offspring.
甾醇生物合成是人体重要的稳态机制。甾醇生物合成始于胚胎早期,并贯穿一生。在美国,许多常用药物每年开出超过2亿次,都有抑制甾醇生物合成的副作用。我们使用高通量液相色谱 - 串联质谱法(LC-MS/MS),评估了1312份匿名孕妇血清样本中羊毛甾醇后甾醇中间体(羊毛甾醇、胆甾烯醇和7-脱氢胆固醇(7-DHC))及胆固醇的水平。对302份显示7-DHC升高的样本,分析了14种已知抑制7-脱氢胆固醇还原酶(DHCR7)并增加7-DHC的药物。在302份显示7-DHC升高的样本中,43份含有可检测水平的具有DHCR7抑制副作用的处方药。特定组合(联合用药)服用多种升高7-DHC的药物可能会加剧对孕妇7-DHC水平的影响,提示可能存在相加或协同效应。由于7-DHC和7-DHC衍生的氧化甾醇有毒,且抑制DHCR7的药物被视为致畸剂,我们的研究结果引发了对孕期使用具有DHCR7抑制副作用的处方药的潜在担忧。孕期有时不可避免地要使用处方药,但选择无DHCR7抑制副作用的药物可能会使孕期更健康,并预防发育中的后代可能出现的不良后果。