Publications by authors named "P van Bladeren"
Estragole is a known hepatocarcinogen in rodents at high doses following metabolic conversion to the DNA-reactive metabolite 1'-sulfooxyestragole. The aim of the present study was to model possible levels of DNA adduct formation in (individual) humans upon exposure to estragole. This was done by extending a previously defined PBK model for estragole in humans to include (i) new data on interindividual variation in the kinetics for the major PBK model parameters influencing the formation of 1'-sulfooxyestragole, (ii) an equation describing the relationship between 1'-sulfooxyestragole and DNA adduct formation, (iii) Monte Carlo modeling to simulate interindividual human variation in DNA adduct formation in the population, and (iv) a comparison of the predictions made to human data on DNA adduct formation for the related alkenylbenzene methyleugenol.
View Article and Find Full Text PDFTo study the effect of metabolic conjugation of flavonoids on the potential to inhibit protein kinase activity, the inhibitory effects of the dietary flavonol kaempferol and its major plasma conjugate kaempferol-3-O-glucuronide on protein kinases were studied. To this end, the inhibition of the phosphorylation activity of recombinant protein kinase A (PKA) and of cell lysate from the hepatocellular carcinoma cell line HepG2 on 141 putative serine/threonine phosphorylation sites derived from human proteins was assessed. Glucuronidation reduced the inhibitory potency of kaempferol on the phosphorylation activity of PKA and HepG2 lysate on average about 16 and 3.
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- Non-prenylated isoflavone aglycones, like genistein and daidzein, have phyto-estrogenic properties and can activate estrogen receptors ERα and ERβ due to their similarity to 17β-estradiol.
- In a study comparing the estrogenic activities of these isoflavones to their glucuronide metabolites, the metabolites were found to be significantly less potent in modulating receptor interactions.
- Interestingly, glucuronidation shifted the activation preference from ERβ to ERα for genistein and increased daidzein's preference for ERα, which could have implications for understanding the health benefits associated with isoflavone consumption.
The consumption of dietary flavonoids has been associated with a variety of health benefits, including effects mediated by the activation of peroxisome proliferator-activated receptor-gamma (PPAR-γ). Flavonoids are extensively metabolized during and after uptake and there is little known on the biological effects of these conjugated metabolites of flavonoids that are found in plasma. To investigate the effect of glucuronidation on the ability of flavonoids to activate PPAR-γ we studied and compared the activity of quercetin, kaempferol and their relevant plasma conjugates quercetin-3-O-glucuronide (Q3G) and kaempferol-3-O-glucuronide (K3G) on different PPAR-γ related endpoints.
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- The study uses Monte Carlo simulations to predict the levels of a carcinogenic metabolite of methyleugenol in humans, considering variability in metabolic reactions.
- The formation of 1'-sulfooxymethyleugenol is primarily influenced by different metabolic pathways and the variability of specific enzymes involved in these processes.
- The results indicate that while a default uncertainty factor can address 90% of human variability, a larger factor is needed for 99%, highlighting the effectiveness of Monte Carlo modeling in assessing interindividual differences in risk evaluations.