Department of Food and Drug, University of Parma, 43124 Parma, Italy.
Wageningen Food Safety Research, P.O. Box 230, 6700 AE Wageningen, The Netherlands.
Toxins (Basel). 2023 Jan 18;15(2):94. doi: 10.3390/toxins15020094.
Safrole, a 162.2 Da natural compound belonging to the alkenylbenzenes class, is classified as a possible carcinogen to humans by IARC (group IIB) and has proven to be genotoxic and carcinogenic to rodents. Despite its use as a food or feed additive, it is forbidden in many countries due to its documented toxicity; yet, it is still broadly present within food and feed and is particularly abundant in spices, herbs and essential oils. Specifically, safrole may exert its toxicity upon bioactivation to its proximate carcinogen 1'-hydroxy-safrole via specific members of the cytochrome P450 protein family with a certain inter/intra-species variability. To investigate this variability, an in-silico workflow based on molecular modelling, docking and molecular dynamics has been successfully applied. This work highlighted the mechanistic basis underpinning differences among humans, cats, chickens, goats, sheep, dogs, mice, pigs, rats and rabbits. The chosen metric to estimate the likeliness of formation of 1'-hydroxy-safrole by the species-specific cytochrome P450 under investigation allowed for the provision of a knowledge-based ground to rationally design and prioritise further experiments and deepen the current understanding of alkenylbenzenes bioactivation and CYPs mechanics. Both are crucial for a more informed framework of analysis for safrole toxicity.
黄樟素，一种 162.2Da 的天然化合物，属于烯基苯类，被 IARC（国际癌症研究机构）归类为对人类可能致癌物质（第 2B 组），已被证明对啮齿动物具有遗传毒性和致癌性。尽管它被用作食品或饲料添加剂，但由于其毒性已被记录在案，许多国家都禁止使用它；然而，它仍然广泛存在于食品和饲料中，特别是在香料、草药和精油中含量丰富。具体来说，黄樟素可能通过特定的细胞色素 P450 蛋白家族成员对其前致癌物质 1'-羟基-黄樟素进行生物活化，从而发挥其毒性，这种生物活化作用具有一定的种间/种内变异性。为了研究这种变异性，成功地应用了一种基于分子建模、对接和分子动力学的计算工作流程。这项工作突出了人类、猫、鸡、山羊、绵羊、狗、老鼠、猪、大鼠和兔子之间差异的机制基础。选择的度量标准用于估计所研究的物种特异性细胞色素 P450 形成 1'-羟基-黄樟素的可能性，为基于知识的合理设计和优先考虑进一步的实验提供了基础，并加深了对烯基苯生物活化和细胞色素 P450 机制的现有理解。这两者对于更明智的黄樟素毒性分析框架都至关重要。
