First evidence of pyrrolizidine alkaloid N-oxide-induced hepatic sinusoidal obstruction syndrome in humans

Abstract

Pyrrolizidine alkaloids (PAs) are among the most potent phytotoxins widely distributed in plant species around the world. PA is one of the major causes responsible for the development of hepatic sinusoidal obstruction syndrome (HSOS) and exerts hepatotoxicity via metabolic activation to form the reactive metabolites, which bind with cellular proteins to generate pyrrole-protein adducts, leading to hepatotoxicity. PA N-oxides coexist with their corresponding PAs in plants with varied quantities, sometimes even higher than that of PAs, but the toxicity of PA N-oxides remains unclear. The current study unequivocally identified PA N-oxides as the sole or predominant form of PAs in 18 Gynura segetum herbal samples ingested by patients with liver damage. For the first time, PA N-oxides were recorded to induce HSOS in human. PA N-oxide-induced hepatotoxicity was further confirmed on mice orally dosed of herbal extract containing 170 μmol PA N-oxides/kg/day, with its hepatotoxicity similar to but potency much lower than the corresponding PAs. Furthermore, toxicokinetic study after a single oral dose of senecionine N-oxide (55 μmol/kg) on rats revealed the toxic mechanism that PA N-oxides induced hepatotoxicity via their biotransformation to the corresponding PAs followed by the metabolic activation to form pyrrole-protein adducts. The remarkable differences in toxicokinetic profiles of PAs and PA N-oxides were found and attributed to their significantly different hepatotoxic potency. The findings of PA N-oxide-induced hepatotoxicity in humans and rodents suggested that the contents of both PAs and PA N-oxides present in herbs and foods should be regulated and controlled in use.

Expert consensus on the clinical management of pyrrolizidine alkaloid‐induced hepatic sinusoidal obstruction syndrome

“…Serum pyrrole protein adducts (PPAs) are of clinical value in suspected PA–HSOS patients with an uncertain history of ingesting PA‐containing . Both PAs and PA N ‐oxides were identified in 18 samples of Gynura segetum ingested by patients with liver damage . A prospective study by Gao et al .…”

“…2,3 Both PAs and PA N-oxides were identified in 18 samples of Gynura segetum ingested by patients with liver damage. 60 A prospective study by Gao et al found that a serum PPA assay correctly distinguished 23 of 40 patients with liver injury and a history of PA-containing medicines from the 17 with liver injury caused by drugs that did not contain PA. 38 The findings indicated that serum PPAs had a diagnostic sensitivity of 100.0%, a specificity of 94.1%, a positive predictive value of 95.8%, and a negative predictive value of 100.0%. Blood PPAs assayed by ultra-high-performance liquid chromatography-triple quadrupole-mass spectrometry can serve as a specific biomarker of PA-induced liver injury.…”

Preoperative Diagnosis of Hepatic Sinus Obstruction Syndrome Caused by Tusanqi and Evaluation of Therapeutic Effects after TIPS by Imaging and Pathology

“…The main reason is that it is easy to use Tusanqi is that it is similar to the precious traditional Chinese medicine Panax notoginseng, which has functions including the promotion of blood circulation, the removal of blood stasis and the relief of swelling and pain. When PAs contained in herbal medicines are ingested into the body, metabolites generated under the catalysis of the hepatic cytochrome P450 enzyme combine with proteins to form pyrrole protein adducts, which damage sinusoidal endothelial cells, cause the exfoliated endothelial cells to aggregate in the central lobular area, and form cell emboli, resulting in intrahepatic congestion, liver function damage and portal hypertension [21][22] . Binding to GSH is one of the most important detoxification reactions of PA.…”

Stability of pyrrolizidine alkaloids from Senecio vernalis in grass silage under different ensilage conditions

“…A broad range of plant species have been identified that produce toxic 1,2‐dehydro‐pyrrolizidine alkaloids (PAs) as secondary metabolites . These PAs are potent phytotoxins exerting hepatotoxicity and carcinogenicity . In recent years, the appearance of Senecio spp.…”

“…1,2 These PAs are potent phytotoxins exerting hepatotoxicity and carcinogenicity. 3,4 In recent years, the appearance of Senecio spp. such as common ragwort (Senecio jacobaea), common groundsel (S. vulgaris), eastern groundsel (S. vernalis) or narrow-leafed ragwort (S. inaequidens) increased on fields used for forage production in Germany and other countries.…”