Department of Internal Medicine II, Division of Gastroenterology and Hepatology, Klinikum Hanau, Teaching Hospital of the Medical Faculty, Goethe University Frankfurt/Main, 63450 Hanau, Germany.
Laboratory of Plant Physiology and Biochemistry, Graduate School of Advanced Science and Engineering, Hiroshima University, Hiroshima 739-8529, Japan.
Int J Mol Sci. 2021 Sep 27;22(19):10419. doi: 10.3390/ijms221910419.
Saturated and unsaturated pyrrolizidine alkaloids (PAs) are present in more than 6000 plant species growing in countries all over the world. They have a typical heterocyclic structure in common, but differ in their potential toxicity, depending on the presence or absence of a double bond between C1 and C2. Fortunately, most plants contain saturated PAs without this double bond and are therefore not toxic for consumption by humans or animals. In a minority of plants, however, PAs with this double bond between C1 and C2 exhibit strong hepatotoxic, genotoxic, cytotoxic, neurotoxic, and tumorigenic potentials. If consumed in error and in large emouns, plants with 1,2-unsaturated PAs induce metabolic breaking-off of the double bonds of the unsaturated PAs, generating PA radicals that may trigger severe liver injury through a process involving microsomal P450 (CYP), with preference of its isoforms CYP 2A6, CYP 3A4, and CYP 3A5. This toxifying CYP-dependent conversion occurs primarily in the endoplasmic reticulum of the hepatocytes equivalent to the microsomal fraction. Toxified PAs injure the protein membranes of hepatocytes, and after passing their plasma membranes, more so the liver sinusoidal endothelial cells (LSECs), leading to life-threatening hepatic sinusoidal obstruction syndrome (HSOS). This injury is easily diagnosed by blood pyrrolizidine protein adducts, which are perfect diagnostic biomarkers, supporting causality evaluation using the updated RUCAM (Roussel Uclaf Causality Assessment Method). HSOS is clinically characterized by weight gain due to fluid accumulation (ascites, pleural effusion, and edema), and may lead to acute liver failure, liver transplantation, or death. In conclusion, plant-derived PAs with a double bond between C1 and C2 are potentially hepatotoxic after metabolic removal of the double bond, and may cause PA-HSOS with a potential lethal outcome, even if PA consumption is stopped.
饱和和不饱和吡咯里西啶生物碱（PAs）存在于全球各国 6000 多种植物中。它们具有共同的典型杂环结构，但由于 C1 和 C2 之间是否存在双键而在潜在毒性上有所不同。幸运的是，大多数植物都含有不含这种双键的饱和 PAs，因此对人类或动物的食用没有毒性。然而，在少数植物中，C1 和 C2 之间存在双键的 PAs 具有强烈的肝毒性、遗传毒性、细胞毒性、神经毒性和致癌性。如果误食且数量较大，具有 1,2-不饱和双键的植物会导致不饱和 PAs 的双键发生代谢断裂，生成 PA 自由基，通过涉及微粒体 P450（CYP）的过程，优先选择其同工酶 CYP 2A6、CYP 3A4 和 CYP 3A5，引发严重的肝损伤。这种毒化的 CYP 依赖性转化主要发生在肝细胞的内质网中，相当于微粒体部分。有毒的 PAs 会损伤肝细胞的蛋白质膜，穿过它们的质膜后，更会损伤肝窦内皮细胞（LSEC），导致危及生命的肝窦阻塞综合征（HSOS）。这种损伤很容易通过血液吡咯里西啶蛋白加合物诊断出来，这些加合物是完美的诊断生物标志物，支持使用更新的 RUCAM（Roussel Uclaf 因果关系评估方法）进行因果关系评估。HSOS 的临床特征是由于液体积聚（腹水、胸腔积液和水肿）而体重增加，可能导致急性肝衰竭、肝移植或死亡。总之，代谢去除双键后，C1 和 C2 之间具有双键的植物源性 PAs 具有潜在的肝毒性，并可能导致具有潜在致命后果的 PA-HSOS，即使停止摄入 PA。
