Iori Silvia, Montanucci Ludovica, D'Onofrio Caterina, Lahtela-Kakkonen Maija, Lucatello Lorena, Bardhi Anisa, Barbarossa Andrea, Capolongo Francesca, Zaghini Anna, Pauletto Marianna, Dacasto Mauro, Giantin Mery
Department of Comparative Biomedicine and Food Science, University of Padua, 35020 Padua, Italy.
Department of Neurology, McGovern Medical School, UTHealth-University of Texas Health Science Centre at Houston, Houston, TX 77030, USA.
Toxins (Basel). 2025 Jun 10;17(6):294. doi: 10.3390/toxins17060294.
CYP1B1 is a key enzyme involved in xenobiotic and endogenous metabolism, yet its physiological role in bovine liver homeostasis remains unclear. In this study, we generated a knockout () bovine hepatocyte-like cell line to indirectly investigate its role in liver function. Transcriptomic analysis revealed alterations in immune regulation, epithelial barrier integrity, and detoxification pathways, with concurrent compensatory upregulation. Beyond its physiological role, CYP1B1 was found to actively participate in Aflatoxin B1 (AFB1) metabolism, a mycotoxin posing significant health risks to humans and livestock. Molecular docking suggested that CYP1B1 facilitates the conversion of AFB1 into AFM1 and AFBO. In agreement with these predictions, cells exposed to AFB1 showed reduced AFM1 production and decreased cytotoxicity. Further transcriptomic analysis indicated that cells exhibited mitigated oxidative stress and inflammatory responses, along with downregulation of , a key enzyme in AFB1 bioactivation. This suggests that KO reduces AFB1 toxicity by directly limiting AFB1 bioactivation and indirectly modulating the broader hepatic CYP network, further limiting the formation of toxic intermediates. These findings provide novel insights into 's function in bovine hepatocytes, highlighting its dual role in maintaining liver homeostasis and mediating AFB1 metabolism. The observed interplay between CYP1B1, CYP1A1, and CYP3A74 underscores the complexity of AFB1 biotransformation and warrants further investigation into the coordinated regulation of xenobiotic metabolism in cattle.
细胞色素P450 1B1（CYP1B1）是一种参与外源性和内源性代谢的关键酶，但其在牛肝脏内稳态中的生理作用仍不清楚。在本研究中，我们构建了一种基因敲除（KO）的牛肝细胞样细胞系，以间接研究其在肝功能中的作用。转录组分析揭示了免疫调节、上皮屏障完整性和解毒途径的改变，同时伴有补偿性上调。除了其生理作用外，还发现CYP1B1积极参与黄曲霉毒素B1（AFB1）的代谢，黄曲霉毒素B1是一种对人类和牲畜健康构成重大风险的霉菌毒素。分子对接表明，CYP1B1促进AFB1转化为AFM1和AFBO。与这些预测一致，暴露于AFB1的KO细胞显示AFM1产量降低且细胞毒性降低。进一步的转录组分析表明，KO细胞表现出氧化应激和炎症反应减轻，同时AFB1生物活化的关键酶下调。这表明KO通过直接限制AFB1生物活化和间接调节更广泛的肝脏CYP网络来降低AFB1毒性，进一步限制有毒中间体的形成。这些发现为KO在牛肝细胞中的功能提供了新的见解，突出了其在维持肝脏内稳态和介导AFB1代谢中的双重作用。观察到的CYP1B1、CYP1A1和CYP3A74之间的相互作用强调了AFB1生物转化的复杂性，值得进一步研究牛中外源性代谢的协调调节。
