Abstract
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.
Highlights
This was proposed, for instance, in an hepatic sinusoidal obstruction syndrome (HSOS) outbreak observed in Ethiopia, confounding variables initially prevailed, because pyrrolizidine alkaloids (PAs)-containing herbs are used as medicines by a majority of the inhabitants in this country [68], and bread was found to be contaminated with PAs originating from the PA-producing Ageratum conyzoides spp. that grows widely in the grain fields as a weed [127]
Scanning electron microscopy images showed dilatation of sinusoids, enlarged and damaged fenestrae, and severe congestion in the liver of the model mouse. These results suggested that sinusoidal injury happened in the model group, similar to human PA-HSOS, but the focus of this study was not on hepatocytes and their possible subcellular alterations
While saturated PAs are commonly harmless, 1,2-unsaturated PAs may become toxic if converted to toxifying PA radicals by removing the double bond between C1 and C2, affecting the liver and causing PA-HSOS
Summary
Patients with acute or chronic liver diseases represent a clinical challenge if toxins are suspected, as possible causes are diverse, such as plant-derived 1,2-unsaturated pyrrolizidine alkaloids (PAs) [1,2,3,4,5,6], various other phytochemicals [7,8,9,10,11], ethanol [12,13,14,15], conventional drugs [16,17,18,19], or industrial aliphatic halogenated hydrocarbons like carbon tetrachloride [20].
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