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- W2075199689 abstract "Pyrrolizidine alkaloids (PAs) are naturally occurring phytochemicals found in plants worldwide. A number of PAs are known to be hepatoxic to humans and may cause fatalities [1]. Consumers may be exposed to PAs through ingestion of contaminated grains or use of dietary supplements. It has been established that the hepatoxicity of many PAs results from their metabolism by hepatic enzymes, including cytochrome P450, to produce reactive pyrroles [2, 3]. In our investigation, metabolism-mediated toxicity of two PAs, retrorsine and monocrotaline, was studied using a co-culture of human hepatocarcinoma (HepG2/C3A) cells and rat liver microsomes. HepG2/C3A cells were incubated with PAs for 6 hrs in the presence and absence of rat liver microsomes and the toxicity was assessed as lowered mitochondrial activity (i.e. mitochondrial reduction of MTT). We found that both retrorsine and monocrotaline were toxic and the toxicity was dependent on microsome-mediated metabolism. In addition, LC/MS was used to measure microsome-mediated metabolism of the PAs and formation of the glutathione conjugates of the resulting reactive pyrroles. The LC/MS measurements indicated that the PAs were rapidly metabolized by rat liver microsomes with concomitant production of reactive pyrroles. The results of the in vitro assay and LC/MS measurements are consistent with metabolism-mediated toxicity for retrorsine and monocrotaline. References: [1] Fu PP, Xia Q, et al. (2004) Drug Metabolism Rev 36: 1–55. [2] Stegelmeier BL, Edgar JA (1999)J Nat Toxins 8: 95–116. [3] Chou MW, Fu PP (2006) Tox Ind Health 22: 321–327." @default.
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- W2075199689 date "2010-03-01" @default.
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- W2075199689 title "Development of an In vitro Co-culture Assay for the Investigation of Metabolism-Mediated Toxicity of Pyrrolizidine Alkaloids" @default.
- W2075199689 doi "https://doi.org/10.1055/s-0030-1251861" @default.
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