Centro de Investigaciones sobre Porfirinas y Porfirias (CIPYP), CONICET, Hospital de Clínicas José de San Martín, Universidad de Buenos Aires, Argentina.
Cátedra de Bromatología y Nutrición, Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral, Santa Fe, Argentina.
Biochim Biophys Acta Gen Subj. 2018 Jun;1862(6):1296-1305. doi: 10.1016/j.bbagen.2018.02.013. Epub 2018 Feb 22.
Acute Intermittent Porphyria (AIP) is an inherited disease produced by a deficiency of Porphobilinogen deaminase (PBG-D). The aim of this work was to evaluate the effects of Isoflurane and Sevoflurane on heme metabolism in a mouse genetic model of AIP to further support our previous proposal for avoiding their use in porphyric patients. A comparative study was performed administering the porphyrinogenic drugs allylisopropylacetamide (AIA), barbital and ethanol, and also between sex and mutation using AIP (PBG-D activity 70% reduced) and T1 (PBG-D activity 50% diminished) mice.
The activities of 5-Aminolevulinic synthetase (ALA-S), PBG-D, Heme oxygenase (HO) and CYP2E1; the expression of ALA-S and the levels of 5-aminolevulinic acid (ALA) were measured in different tissues of mice treated with the drugs mentioned.
Isoflurane increased liver, kidney and brain ALA-S activity of AIP females but only affected kidney AIP males. Sevoflurane induced ALA-S activity in kidney and brain of female AIP group. PBG-D activity was further reduced by Isoflurane in liver male T1; in AIP male mice activity remained in its low basal levels. Ethanol and barbital also caused biochemical alterations. Only AIA triggered neurological signs similar to those observed during human acute attacks in male AIP being the symptoms less pronounced in females although ALA-S induction was greater. Heme degradation was affected.
Biochemical alterations caused by the porphyrinogenic drugs assayed were different in male and female mice and also between T1 and AIP being more affected the females of AIP group.
This is the first study using volatile anaesthetics in an AIP genetic model confirming Isoflurane and Sevoflurane porphyrinogenicity.
急性间歇性卟啉症（AIP）是一种由卟胆原脱氨酶（PBG-D）缺乏引起的遗传性疾病。本工作的目的是评估异氟烷和七氟烷对 AIP 小鼠遗传模型中血红素代谢的影响，以进一步支持我们先前避免在卟啉症患者中使用它们的建议。进行了一项比较研究，给予卟啉原生成药物丙烯基异丙基乙酰胺（AIA）、巴比妥和乙醇，还使用 AIP（PBG-D 活性降低 70%）和 T1（PBG-D 活性降低 50%）小鼠比较了性别和突变的影响。
测定了不同组织中 5-氨基酮戊酸合酶（ALA-S）、PBG-D、血红素氧合酶（HO）和 CYP2E1 的活性；ALA-S 的表达以及 5-氨基酮戊酸（ALA）的水平。
异氟烷增加了 AIP 雌性小鼠的肝脏、肾脏和大脑的 ALA-S 活性，但仅影响了 AIP 雄性小鼠的肾脏。七氟烷诱导了雌性 AIP 组肾脏和大脑中的 ALA-S 活性。异氟烷进一步降低了 T1 雄性肝脏中的 PBG-D 活性；在 AIP 雄性小鼠中，活性仍保持在较低的基础水平。乙醇和巴比妥也引起了生化改变。只有 AIA 引起了类似于人类急性发作时观察到的神经症状，而雌性小鼠的症状较轻，尽管 ALA-S 诱导更强。血红素降解受到影响。
所测定的卟啉原生成药物引起的生化改变在雄性和雌性小鼠以及 T1 和 AIP 之间不同，AIP 组的雌性受影响更大。
这是首次在 AIP 遗传模型中使用挥发性麻醉剂进行的研究，证实了异氟烷和七氟烷的卟啉原生成性。
