Cytochrome P450 2E1 (CYP2E1) is a key target protein in the development of alcoholic and nonalcoholic fatty liver disease (FLD). The pathophysiological correlate is the massive production of reactive oxygen species. The role of CYP2E1 in the development of hepatocellular carcinoma (HCC), the final complication of FLD, remains controversial. Specifically, CYP2E1 has not yet been defined as a molecular target for HCC therapy. In addition, a CYP2E1-specific drug has not been developed. We have already shown that our newly developed CYP2E1 inhibitor 12-imidazolyl-1-dodecanol (I-ol) was therapeutically effective against alcoholic and nonalcoholic steatohepatitis. In this study, we investigated the effect of I-ol on HCC tumorigenesis and whether I-ol could serve as a possible treatment option for terminal-stage FLD. I-ol exerted a very highly significant antitumour effect against hepatocellular HepG2 cells. Cell viability was reduced in a dose-dependent manner, with only the highest doses causing a cytotoxic effect associated with caspase 3/7 activation. Comparable results were obtained for the model colorectal adenocarcinoma cell line, DLD-1, whose tumorigenesis is also associated with CYP2E1. Transcriptome analyses showed a clear effect of I-ol on apoptosis and cell-cycle regulation, with the increased expression of p27Kip1 being particularly noticeable. These observations were confirmed at the protein level for HepG2 and DLD-1 cells grafted on a chorioallantoic membrane. Cell-cycle analysis showed a complete loss of proliferating cells with a simultaneous increase in S-phase arrest beginning at a threshold dose of 30 μM. I-ol also reduced xenograft tumour growth in nude mice. This antitumour effect was not associated with tumour cachexia. I-ol was not toxic to healthy tissues or organs. This study demonstrates for the first time the therapeutic effect of the specific CYP2E1 inhibitor I-ol on the tumorigenesis of HCC. Our findings imply that I-ol can potentially be applied therapeutically on patients at the final stage of FLD.

中文翻译：

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一种新的 CYP2E1 抑制剂，12-Imidazolyl-1-dodecanol，代表了一种潜在的肝细胞癌治疗方法

细胞色素 P450 2E1 (CYP2E1) 是酒精性和非酒精性脂肪肝 (FLD) 发展中的关键靶蛋白。病理生理学相关是活性氧的大量产生。CYP2E1 在肝细胞癌 (HCC)（FLD 的最终并发症）发展中的作用仍然存在争议。具体而言，CYP2E1 尚未被定义为 HCC 治疗的分子靶点。此外，尚未开发出 CYP2E1 特异性药物。我们已经证明，我们新开发的 CYP2E1 抑制剂 12-咪唑基-1-十二醇 (I-ol) 对酒精性和非酒精性脂肪性肝炎具有治疗效果。在这项研究中，我们研究了 I-ol 对 HCC 肿瘤发生的影响，以及 I-ol 是否可以作为晚期 FLD 的可能治疗选择。I-ol 对肝细胞 HepG2 细胞具有非常显着的抗肿瘤作用。细胞活力以剂量依赖性方式降低，只有最高剂量会引起与 caspase 3/7 激活相关的细胞毒性作用。模型结直肠腺癌细胞系 DLD-1 获得了类似的结果，其肿瘤发生也与 CYP2E1 相关。转录组分析显示 I-ol 对细胞凋亡和细胞周期调节有明显影响，其中 p27Kip1 的表达增加尤为明显。这些观察结果在移植到绒毛膜尿囊膜上的 HepG2 和 DLD-1 细胞的蛋白质水平上得到证实。细胞周期分析显示，在阈值剂量为 30 μ M. I-ol 还降低了裸鼠中的异种移植肿瘤生长。这种抗肿瘤作用与肿瘤恶病质无关。I-ol 对健康组织或器官没有毒性。本研究首次证明了特异性 CYP2E1 抑制剂 I-ol 对 HCC 肿瘤发生的治疗作用。我们的研究结果表明 I-ol 有可能在 FLD 的最后阶段对患者进行治疗。