Structure-Dependent Toxicokinetics of Selected Pyrrolizidine Alkaloids In Vitro

Abstract

Phytochemicals like pyrrolizidine alkaloids (PAs) can affect the health of humans and animals. PAs can occur for example in tea, honey or herbs. Some PAs are known to be cytotoxic, genotoxic, and carcinogenic. Upon intake of high amounts, hepatotoxic and pneumotoxic effects were observed in humans. This study aims to elucidate different toxicokinetic parameters like the uptake of PAs and their metabolism with in vitro models. We examined the transport rates of differently structured PAs (monoester, open-chained diester, cyclic diester) over a model of the intestinal barrier. After passing the intestinal barrier, PAs reach the liver, where they are metabolized into partially instable electrophilic metabolites interacting with nucleophilic centers. We investigated this process by the usage of human liver, intestinal, and lung microsomal preparations for incubation with different PAs. These results are completed with the detection of apoptosis as indicator for bioactivation of the PAs. Our results show a structure-dependent passage of PAs over the intestinal barrier. PAs are structure-dependently metabolized by liver microsomes and, to a smaller extent, by lung microsomes. The detection of apoptosis of A549 cells treated with lasiocarpine and monocrotaline following bioactivation by human liver or lung microsomes underlines this result. Conclusively, our results help to shape the picture of PA toxicokinetics which could further improve the knowledge of molecular processes leading to observed effects of PAs in vivo.

Pyrrolizidine Alkaloids—Pros and Cons for Pharmaceutical and Medical Applications

“…After applying lasiocarpine and monocrotaline, apoptosis in the alveolar basal epithelial adenocarcinoma A549 cell line was detected. Such findings may contribute to a better understanding of molecular processes leading to the effects of PAs observed in in vivo studies [96].…”

“…2023, 24, x FOR PEER REVIEW 18 of 32 adenocarcinoma A549 cell line was detected. Such findings may contribute to a better understanding of molecular processes leading to the effects of PAs observed in in vivo studies [96].…”

“…Various toxicokinetic parameters of PAs were elucidated. The transport rates of differently structured PAs (monoesters, open-chained diesters, and cyclic diesters) were studied in in vitro models [96]. It was shown that PAs are metabolized by liver microsomes in a structure-dependent manner and, to a lesser extent, by lung microsomes.…”

“…Secondly, how the transport of the substance through the intestine takes place in addition to absorption is crucial. The absorption pathway in the liver and the activation of the complicated metabolic pathways should also be emphasized [96].…”

Analysis of potential risks of clinical application of Yi Dian Hong and its proprietary Chinese medicines: A review

“…Culvenor et al’s study suggests that this phenomenon is associated with low levels of PAs (0.025 mmol/kg body weight) and prolonged exposure. [38] This extended exposure resulted in 2 distinct types of lung lesions: one characterized by intravascular aggregates of single nucleated cells, ultimately leading to venous occlusion; and the other exhibiting extravascular changes, including thickening of the alveolar septa and an increased cell count. In a clinical case report, a 66-year-old woman developed progressive dyspnea after long-term consumption of herbal tea containing comfrey ingredients and was diagnosed with PAH.…”