van den Berg Suzanne J P L, Klaus Verena, Alhusainy Wasma, Rietjens Ivonne M C M
Division of Toxicology, Wageningen University, Tuinlaan 5, 6703 HE Wageningen, The Netherlands.
Food Chem Toxicol. 2013 Dec;62:32-40. doi: 10.1016/j.fct.2013.08.019. Epub 2013 Aug 16.
Basil-containing plant food supplements (PFS) can contain estragole which can be metabolised into a genotoxic and carcinogenic 1'-sulfoxymetabolite. This study describes the inhibition of sulfotransferase (SULT)-mediated bioactivation of estragole by compounds present in basil-containing PFS. Results reveal that PFS consisting of powdered basil material contain other compounds with considerable in vitro SULT-inhibiting activity, whereas the presence of such compounds in PFS consisting of basil essential oil was limited. The inhibitor in powdered basil PFS was identified as nevadensin. Physiologically based kinetic (PBK) modeling was performed to elucidate if the observed inhibitory effects can occur in vivo. Subsequently, risk assessment was performed using the Margin of Exposure (MOE) approach. Results suggest that the consequences of the in vivo matrix-derived combination effect are significant when estragole would be tested in rodent bioassays with nevadensin at ratios detected in PFS, thereby increasing MOE values. However, matrix-derived combination effects may be limited at lower dose levels, indicating that the importance of matrix-derived combination effects for risk assessment of individual compounds should be done on a case-by-case basis considering dose-dependent effects. Furthermore, this study illustrates how PBK modeling can be used in risk assessment of PFS, contributing to further reduction in the use of experimental animals.
含罗勒的植物性食品补充剂（PFS）可能含有草蒿脑，草蒿脑可代谢为具有基因毒性和致癌性的1'-亚磺氧基代谢物。本研究描述了含罗勒的PFS中存在的化合物对磺基转移酶（SULT）介导的草蒿脑生物活化的抑制作用。结果显示，由罗勒粉末制成的PFS含有其他具有显著体外SULT抑制活性的化合物，而由罗勒精油制成的PFS中此类化合物的含量有限。罗勒粉末PFS中的抑制剂被鉴定为内华达ensin。进行了基于生理学的动力学（PBK）建模，以阐明观察到的抑制作用是否会在体内发生。随后，使用暴露边际（MOE）方法进行了风险评估。结果表明，当在啮齿动物生物测定中以PFS中检测到的比例用内华达ensin测试草蒿脑时，体内基质衍生的联合效应的后果是显著的，从而增加了MOE值。然而，在较低剂量水平下，基质衍生的联合效应可能有限，这表明对于单个化合物的风险评估，应根据剂量依赖性效应逐案确定基质衍生联合效应的重要性。此外，本研究说明了PBK建模如何可用于PFS的风险评估，有助于进一步减少实验动物的使用。
