PDF(Pubmed)
Abstract：
UNASSIGNED: Cinnamic alcohol is a natural compound, widely used in fragrances, which can cause allergic contact dermatitis. Cinnamic alcohol lacks intrinsic reactivity and autoxidation or metabolic activation is necessary for it to act as a sensitizer.
UNASSIGNED: Bioactivation of cinnamic alcohol was explored using human liver microsomes, human liver S9 and SkinEthic™ Reconstructed Human Epidermis. A targeted multiple reaction monitoring mass spectrometry method was employed to study and quantify cinnamic alcohol along with eight potential phase I or phase II metabolites. The reconstructed human epidermis model, treated with cinnamic alcohol, was also analyzed with a non-targeted high-resolution mass spectrometry method to identify metabolites not included in the targeted method.
UNASSIGNED: Two metabolites identified with the targeted method, namely, pOH-cinnamic alcohol and pOH-cinnamic aldehyde, have not previously been identified in a metabolic in vitro system. Their reactivity toward biologically relevant nucleophiles was investigated and compared to their sensitizing potency in vivo in the murine local lymph node assay (LLNA). According to the LLNA, the pOH-cinnamic alcohol is non-sensitizing and pOH-cinnamic aldehyde is a moderate sensitizer. This makes pOH-cinnamic aldehyde less sensitizing than cinnamic aldehyde, which has been found to be a strong sensitizer in the LLNA. This difference in sensitizing potency was supported by the reactivity experiments. Cinnamic sulfate, previously proposed as a potential reactive metabolite of cinnamic alcohol, was not detected in any of the incubations. In addition, experiments examining the reactivity of cinnamic sulfate toward a model peptide revealed no evidence of adduct formation. The only additional metabolite that could be identified with the non-targeted method was a dioxolan derivative. Whether or not this metabolite, or one of its precursors, could contribute to the sensitizing potency of cinnamic alcohol would need further investigation.
UNASSIGNED: Cinnamic alcohol is one of the most common fragrance allergens and as it is more effective to patch test with the actual sensitizer than with the prohapten itself, it is important to identify metabolites with sensitizing potency. Further, improved knowledge of metabolic transformations occurring in the skin can improve prediction models for safety assessment of skin products.
UNASSIGNED: Bioactivation of cinnamic alcohol was explored using human liver microsomes, human liver S9 and SkinEthic™ Reconstructed Human Epidermis. A targeted multiple reaction monitoring mass spectrometry method was employed to study and quantify cinnamic alcohol along with eight potential phase I or phase II metabolites. The reconstructed human epidermis model, treated with cinnamic alcohol, was also analyzed with a non-targeted high-resolution mass spectrometry method to identify metabolites not included in the targeted method.
UNASSIGNED: Two metabolites identified with the targeted method, namely, pOH-cinnamic alcohol and pOH-cinnamic aldehyde, have not previously been identified in a metabolic in vitro system. Their reactivity toward biologically relevant nucleophiles was investigated and compared to their sensitizing potency in vivo in the murine local lymph node assay (LLNA). According to the LLNA, the pOH-cinnamic alcohol is non-sensitizing and pOH-cinnamic aldehyde is a moderate sensitizer. This makes pOH-cinnamic aldehyde less sensitizing than cinnamic aldehyde, which has been found to be a strong sensitizer in the LLNA. This difference in sensitizing potency was supported by the reactivity experiments. Cinnamic sulfate, previously proposed as a potential reactive metabolite of cinnamic alcohol, was not detected in any of the incubations. In addition, experiments examining the reactivity of cinnamic sulfate toward a model peptide revealed no evidence of adduct formation. The only additional metabolite that could be identified with the non-targeted method was a dioxolan derivative. Whether or not this metabolite, or one of its precursors, could contribute to the sensitizing potency of cinnamic alcohol would need further investigation.
UNASSIGNED: Cinnamic alcohol is one of the most common fragrance allergens and as it is more effective to patch test with the actual sensitizer than with the prohapten itself, it is important to identify metabolites with sensitizing potency. Further, improved knowledge of metabolic transformations occurring in the skin can improve prediction models for safety assessment of skin products.
摘要：
■肉桂醇是一种天然化合物，广泛用于香料，会引起过敏性接触性皮炎.肉桂醇缺乏固有的反应性,并且自氧化或代谢活化对于其充当敏化剂是必要的。
■使用人肝微粒体探索肉桂醇的生物活化，人类肝脏S9和SkinEthic™重建人类表皮。采用有针对性的多反应监测质谱方法来研究和定量肉桂醇以及八种潜在的I相或II相代谢物。重建的人类表皮模型，用肉桂酸酒精治疗，还使用非靶向高分辨率质谱方法进行分析，以鉴定不包括在靶向方法中的代谢物。
■用靶向方法鉴定的两种代谢物，即,pOH-肉桂醇和pOH-肉桂醛，以前没有在体外代谢系统中鉴定。研究了它们对生物相关亲核试剂的反应性，并在鼠局部淋巴结测定（LLNA）中与它们的体内敏化效力进行了比较。根据LLNA，pOH-肉桂醇是非敏化的,并且pOH-肉桂醛是中等敏化剂。这使得pOH-肉桂醛比肉桂醛更不敏感，已被发现是LLNA中的强敏化剂。这种敏化效力的差异得到反应性实验的支持。硫酸肉桂酸,先前提出作为肉桂酸醇的潜在活性代谢产物，在任何孵育中均未检测到。此外,检查硫酸肉桂酸对模型肽的反应性的实验显示没有加合物形成的证据。可以用非靶向方法鉴定的唯一另外的代谢物是二氧戊环衍生物。不管这种代谢物是否，或者它的前体之一，可能有助于肉桂醇的致敏效力需要进一步研究。
■肉桂醇是最常见的香料过敏原之一，因为用实际敏化剂进行贴片测试比使用前半抗原本身更有效，鉴定具有致敏效力的代谢物是重要的。Further,改善皮肤中发生的代谢转化的知识可以改善皮肤产品安全性评估的预测模型。
■使用人肝微粒体探索肉桂醇的生物活化，人类肝脏S9和SkinEthic™重建人类表皮。采用有针对性的多反应监测质谱方法来研究和定量肉桂醇以及八种潜在的I相或II相代谢物。重建的人类表皮模型，用肉桂酸酒精治疗，还使用非靶向高分辨率质谱方法进行分析，以鉴定不包括在靶向方法中的代谢物。
■用靶向方法鉴定的两种代谢物，即,pOH-肉桂醇和pOH-肉桂醛，以前没有在体外代谢系统中鉴定。研究了它们对生物相关亲核试剂的反应性，并在鼠局部淋巴结测定（LLNA）中与它们的体内敏化效力进行了比较。根据LLNA，pOH-肉桂醇是非敏化的,并且pOH-肉桂醛是中等敏化剂。这使得pOH-肉桂醛比肉桂醛更不敏感，已被发现是LLNA中的强敏化剂。这种敏化效力的差异得到反应性实验的支持。硫酸肉桂酸,先前提出作为肉桂酸醇的潜在活性代谢产物，在任何孵育中均未检测到。此外,检查硫酸肉桂酸对模型肽的反应性的实验显示没有加合物形成的证据。可以用非靶向方法鉴定的唯一另外的代谢物是二氧戊环衍生物。不管这种代谢物是否，或者它的前体之一，可能有助于肉桂醇的致敏效力需要进一步研究。
■肉桂醇是最常见的香料过敏原之一，因为用实际敏化剂进行贴片测试比使用前半抗原本身更有效，鉴定具有致敏效力的代谢物是重要的。Further,改善皮肤中发生的代谢转化的知识可以改善皮肤产品安全性评估的预测模型。
