Erryana Martati, Rungnapa Boonpawa, Johannes H.J. van den Berg, Alicia Paini, Albertus Spenkelink, Ans Punt, Jacques Vervoort, Peter J. van Bladeren, Ivonne M.C.M. Rietjens
Safrole, present in mace and its essential oils, causes liver tumors in rodents at high dose levels due to formation of a DNA reactive 1'-sulfooxysafrole. The present study identifies malabaricone C as a mace constituent able to inhibit safrole DNA adduct formation at the level of sulfotransferase mediated bioactivation. This inhibition was incorporated into physiologically based biokinetic rat and human models. Dosing safrole at 50. mg/kg body weight and malabaricone C-containing mace extract at a ratio reflecting the relative presence in mace, and assuming 100% or 1% uptake of malabaricone C-containing mace extract, the model predicted inhibition of 1'-sulfooxysafrole formation for rats and humans by 90% and 100% or 61% and 91%, respectively. To validate the model, mace extract and safrole were co-administered orally to Sprague-Dawley rats. LC-ECI-MS/MS based quantification of DNA adduct levels revealed a significant (p<. 0.01) 55% reduction of safrole DNA adduct formation by malabaricone C-containing mace extract in the liver of rats exposed to safrole. The data obtained were used to perform a refined risk assessment of safrole. Overall, the results suggest a lower tumor incidence when safrole would be tested within a relevant food matrix containing sulfotransferase inhibitors compared to dosing pure safrole. © 2014 Elsevier Ltd.
Division of Toxicology, Wageningen University, 6703 HE Wageningen, Tuinlaan 5, Netherlands; Department of Food Science and Technology, Brawijaya University, Malang 65145, Jl. Veteran, Indonesia; Department of Biochemistry, Wageningen University, 6703 HA Wageningen, Dreijenlaan 3, Netherlands; Nestlé Research Centre, Lausanne, Vers-Chez-Les-Blanc, Switzerland; Department of Food Science and Technology, Faculty of Agricultural Technology, Brawijaya University, Malang 65145, Jl. Veteran, Indonesia
