Abstract
Pyrrolizidine alkaloids (PA) exert their toxic effects only after bioactivation. Although their toxicity has already been studied and metabolic pathways including important metabolites were described, the quantification of the latter revealed a large unknown portion of the metabolized PA. In this study, the qualitative and quantitative metabolite profiles of structurally different PAs in rat and human liver microsomes were investigated. Between five metabolites for europine and up to 48 metabolites for lasiocarpine were detected. Proposals for the chemical structure of each metabolite were derived based on fragmentation patterns using high-resolution mass spectrometry. The metabolite profiles of the diester PAs showed a relatively good agreement between both species. The metabolic reactions were summarized into three groups: dehydrogenation, oxygenation, and shortening of necic acid(s). While dehydrogenation of the necine base is considered as bioactivation, both other routes are considered as detoxification steps. The most abundant changes found for open chained diesters were dealkylations, while the major metabolic pathway for cyclic diesters was oxygenation especially at the nitrogen atom. In addition, all diester PAs formed several dehydrogenation products, via the insertion of a second double bond in the necine base, including the formation of glutathione conjugates. In rat liver microsomes, all investigated PAs formed dehydropyrrolizidine metabolites with the highest amount formed by lasiocarpine, whereas in human liver microsomes, these metabolites could only be detected for diesters. Our findings demonstrate that an extensive analysis of PA metabolism can provide the basis for a better understanding of PA toxicity and support future risk assessment.
Highlights
Pyrrolizidine alkaloids (PA) are a large group of phytotoxins which are found worldwide in about 3% of all flowering plants (Smith and Culvenor 1981)
None of the metabolites was detected in the controls, indicating that all of them were formed in a cytochrome P450 enzyme (CYP)- and nicotinamide adenine dinucleotide phosphate (NADPH)-dependent manner
As pyrrolic metabolites are suspected to play a crucial role in tumor initiation, our results gave a special focus on this metabolic pathway
Summary
Pyrrolizidine alkaloids (PA) are a large group of phytotoxins which are found worldwide in about 3% of all flowering plants (Smith and Culvenor 1981). Due to their high structural diversity, over 660 different PAs and PA N oxides have been identified (Fu et al 2002). Some of the PAs are hepatotoxic and responsible for cases of poisoning in humans and livestock via cytochrome P450 enzyme (CYP)-mediated metabolic activation (Mohabbat et al 1976; Molyneux et al 2011; Tandon et al 1976). The biotransformation rate of PAs, more precisely the extent of metabolic activation versus detoxification, may significantly influence their toxicity.
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