title: Malabaricone C-containing mace extract inhibits safrole bioactivation and DNA adduct formation both in vitro and in vivo.
abstract: 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 50mg/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.
authors: Division of Toxicology, Wageningen University, Tuinlaan 5, 6703 HE Wageningen, The Netherlands; Department of Food Science and Technology, Brawijaya University, Jl. Veteran, Malang 65145, Indonesia. Electronic address: erryana_m@yahoo.com.
authors: Erryana
authors: E
authors: Martati
authors: Division of Toxicology, Wageningen University, Tuinlaan 5, 6703 HE Wageningen, The Netherlands.
authors: Rungnapa
authors: R
authors: Boonpawa
authors: Division of Toxicology, Wageningen University, Tuinlaan 5, 6703 HE Wageningen, The Netherlands.
authors: Johannes H J
authors: JH
authors: van den Berg
authors: Division of Toxicology, Wageningen University, Tuinlaan 5, 6703 HE Wageningen, The Netherlands.
authors: Alicia
authors: A
authors: Paini
authors: Division of Toxicology, Wageningen University, Tuinlaan 5, 6703 HE Wageningen, The Netherlands.
authors: Albertus
authors: A
authors: Spenkelink
authors: Division of Toxicology, Wageningen University, Tuinlaan 5, 6703 HE Wageningen, The Netherlands.
authors: Ans
authors: A
authors: Punt
authors: Department of Biochemistry, Wageningen University, Dreijenlaan 3, 6703 HA Wageningen, The Netherlands.
authors: Jacques
authors: J
authors: Vervoort
authors: Division of Toxicology, Wageningen University, Tuinlaan 5, 6703 HE Wageningen, The Netherlands; Nestlé Research Centre, Vers-Chez-Les-Blanc, Lausanne, Switzerland.
authors: Peter J
authors: PJ
authors: van Bladeren
authors: Division of Toxicology, Wageningen University, Tuinlaan 5, 6703 HE Wageningen, The Netherlands.
authors: Ivonne M C M
authors: IM
authors: Rietjens
mesh_terms: D000818:Animals; D002851:Chromatography, High Pressure Liquid; D018736:DNA Adducts / Q000096:biosynthesis*; D006801:Humans; D066298:In Vitro Techniques; D066244:Proton Magnetic Resonance Spectroscopy; D051381:Rats; D017207:Rats, Sprague-Dawley; D012118:Resorcinols / Q000494:pharmacology*; D012451:Safrole / Q000493:pharmacokinetics*; D053719:Tandem Mass Spectrometry
chemical_list: D018736:DNA Adducts; D012118:Resorcinols; C071787:malabaricone C; D012451:Safrole
keywords: In vitro; In vivo; Mace; PBBK model; Safrole; Safrole DNA adduct