Dorne Jean Lou C M, Cirlini Martina, Louisse Jochem, Pedroni Lorenzo, Galaverna Gianni, Dellafiora Luca
Scientific Committee and Emerging Risks Unit, European Food Safety Authority, Via Carlo Magno 1A, 43124 Parma, Italy.
Department of Food and Drug, University of Parma, 43124 Parma, Italy.
Toxins (Basel). 2022 Mar 14;14(3):207. doi: 10.3390/toxins14030207.
Cytochrome P-450 (CYP) enzymes have a key role in the metabolism of xenobiotics of food origin, and their highly polymorphic nature concurs with the diverse inter-individual variability in the toxicokinetics (TK) and toxicodynamics (TD) of food chemicals. Ochratoxin A is a well-known mycotoxin which contaminates a large variety of food and is associated with food safety concerns. It is a minor substrate of CYP2D6, although the effects of CYP2D6 polymorphisms on its metabolism may be overlooked. Insights on this aspect would provide a useful mechanistic basis for a more science-based hazard assessment, particularly to integrate inter-individual differences in CYP2D6 metabolism. This work presents a molecular modelling approach for the analysis of mechanistic features with regard to the metabolic capacity of CYP2D6 variants to oxidise a number of substrates. The outcomes highlighted that a low-frequency CYP2D6 variant (CYP2D6*110) is likely to enhance ochratoxin A oxidation with possible consequences on TK and TD. It is therefore recommended to further analyse such TK and TD consequences. Generally speaking, we propose the identification of mechanistic features and parameters that could provide a semi-quantitative means to discriminate ligands based on the likelihood to undergo transformation by CYP2D6 variants. This would support the development of a fit-for-purpose pipeline which can be extended to a tool allowing for the bulk analysis of a large number of compounds. Such a tool would ultimately include inter-phenotypic differences of polymorphic xenobiotic-metabolising enzymes in the hazard assessment and risk characterisation of food chemicals.
细胞色素P-450（CYP）酶在食物来源的外源性物质代谢中起关键作用，其高度多态性与食品化学物质的毒代动力学（TK）和毒效动力学（TD）中个体间的多样性差异相一致。赭曲霉毒素A是一种广为人知的霉菌毒素，它污染多种食物，并引发食品安全问题。它是CYP2D6的次要底物，尽管CYP2D6基因多态性对其代谢的影响可能被忽视。在这方面的见解将为更基于科学的危害评估提供有用的机制基础，特别是整合CYP2D6代谢中的个体差异。这项工作提出了一种分子建模方法，用于分析CYP2D6变体氧化多种底物的代谢能力的机制特征。结果表明，一种低频CYP2D6变体（CYP2D6*110）可能会增强赭曲霉毒素A的氧化，对TK和TD可能产生影响。因此，建议进一步分析此类TK和TD后果。一般来说，我们建议识别能够提供半定量方法的机制特征和参数，以便根据被CYP2D6变体转化的可能性来区分配体。这将支持开发一种适用的流程，该流程可扩展为一种工具，用于大量化合物的批量分析。这样的工具最终将在食品化学物质的危害评估和风险表征中纳入多态性外源性物质代谢酶的表型间差异。
