Physiologically Based Biokinetic (PBBK) Modeling of Safrole Bioactivation and Detoxification in Humans as Compared With Rats

Abstract

A physiologically based biokinetic (PBBK) model for the alkenylbenzene safrole in humans was developed based on in vitro- and in silico-derived kinetic parameters. With the model obtained, the time- and dose-dependent formation of the proximate and ultimate carcinogenic metabolites, 1-hydroxysafrole and 1-sulfooxysafrole in human liver were estimated and compared with previously predicted levels of these metabolites in rat liver. In addition, Monte Carlo simulations were performed to predict interindividual variation in the formation of these metabolites in the overall population. For the evaluation of the model performance, a comparison was made between the predicted total amount of urinary metabolites of safrole and the reported total levels of metabolites in the urine of humans exposed to safrole, which adequately matched. The model results revealed no dose-dependent shifts in safrole metabolism and no relative increase in bioactivation at dose levels up to 100mg/kg body weight/day. Species differences were mainly observed in the detoxification pathways of 1-hydroxysafrole, with the formation of 1-oxosafrole being a main detoxification pathway of 1-hydroxysafrole in humans but a minor pathway in rats, and glucuronidation of 1-hydroxysafrole being less important in humans than in rats. The formation of 1-sulfooxysafrole was predicted to vary 4- to 17-fold in the population (fold difference between the 95th and median, and 95th and 5th percentile, respectively), with the median being three to five times higher in human than in rat liver. Comparison of the PBBK results for safrole with those previously obtained for the related alkenylbenzenes estragole and methyleugenol revealed that differences in 1-sulfooxy metabolite formation are limited, being only twofold to fivefold.

Determination and risk assessment of naturally occurring genotoxic and carcinogenic alkenylbenzenes in nutmeg-based plant food supplements

“…Assuming equal potency of the alkenylbenzenes, combined EDI values obtained ranged from 1.5 to 631 μg kg −1 bw per day resulting in MOE values ranging from 3 to 1309 for the samples in which more than one alkenylbenzene was detected. Using a TEQ concept with TEF values based on in vitro and in vivo data (Miller et al, ; Randerath et al, ; Punt et al, ; Al‐Subeihi et al, ; Martati et al, ; van den Berg et al, ; Alajlouni et al, ; Al‐Malahmeh et al, ), combined EDI values ranged from 0.4 to 295 μg safrole equivalents kg −1 bw leading to MOE values ranging from 6 to 5020. MOE values resulting from both these combined exposure assessments were up to fivefold lower than the MOE values obtained when considering individual exposure to alkenylbenzenes.…”

“…This metabolite is unstable and reacts with DNA. Studies using PBK modelling revealed that the bioactivation of alkenylbenzenes to their ultimate carcinogenic 1 0 -sulfooxy metabolites is linear with the dose, from dose levels as low as levels of realistic human dietary intake up to dose levels as high as the BMD 10 inducing liver tumours in rodent bioassays (Punt et al, 2009;Rietjens et al, 2010;Al-Subeihi et al, 2012;Martati et al, 2012). The mutagenic potential of alkenylbenzenes DNA adducts has not been extensively quantified so far.…”

“…The first one was the slope of the dose–response curve for DNA‐adduct formation in female CD‐1 mice liver upon exposure to different alkenylbenzenes (Randerath et al, ). The second one, was the in vivo level of formation of the hepatocarcinogenic 1′‐sulfoxymetabolite of the different alkenylbenzenes predicted using human physiologically based kinetic (PBK) models at a dose level of 0.01 mg kg −1 bw (Punt et al, ; Al‐Subeihi et al, ; Martati et al, ; van den Berg et al, ; Alajlouni et al, ; Al‐Malahmeh et al, ). A third value was defined based on the BMDL 10 values derived from in vivo tumour data for safrole, estragole and methyleugenol (Miller et al, ), and by read‐across from safrole for myristicin and apiol (Alajlouni et al, ; Al‐Malahmeh et al, ), or by read‐across from methyleugenol and estragole for elemicin (van den Berg et al, ).…”

Physiologically based kinetic modeling of the bioactivation of myristicin

“…For this purpose, the previously defined PBK models for safrole described by Martati et al (2011, 2012) for rat and human were used. For the comparison, the models describing the metabolism of myristicin and safrole were run for a period of 720 h.…”

Lebensmittelchemie 2013

“…—13 Nach Inkubation der humanen Leberkrebszelllinie HepG2 war die Rate für die Bildung von DNA‐Addukten, bezogen auf 108 Nukleotide, mit Methyleugenol am höchsten, gefolgt von Estragol und Safrol (alle drei Substanzen wurden in gleichen Konzentrationen eingesetzt). Diese Ergebnisse stehen im Einklang mit In‐vivo‐Daten über die Bildung von DNA‐Addukten in der Leber nach Behandlung von Mäusen mit Estragol, Safrol und weiteren natürlichen Phenylpropanide 14.…”