Ghanayem Burhan I
Laboratory of Pharmacology and Chemistry, National Toxicology Program, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.
Toxicol Sci. 2007 Feb;95(2):331-9. doi: 10.1093/toxsci/kfl158. Epub 2006 Nov 8.
Urethane is an established animal carcinogen and has been classified as "reasonably anticipated to be a human carcinogen." Until recently, urethane metabolism via esterase was considered the main metabolic pathway of this chemical. However, recent studies in this laboratory showed that CYP2E1, and not esterase, is the primary enzyme responsible for urethane oxidation. Subsequent studies demonstrated significant inhibition of urethane-induced genotoxicity and cell proliferation in Cyp2e1-/- compared to Cyp2e1+/+ mice. Using Cyp2e1-/- mice, current studies were undertaken to assess the relationships between urethane metabolism and carcinogenicity. Urethane was administered via gavage at 1, 10, or 100 mg/kg/day, 5 days/week, for 6 weeks. Animals were kept without chemical administration for 7 months after which they were euthanized, and urethane carcinogenicity was assessed. Microscopic examination showed a significant reduction in the incidences of liver hemangiomas and hemangiosarcomas in Cyp2e1-/- compared to Cyp2e+/+ mice. Lung nodules increased in a dose-dependent manner and were less prevalent in Cyp2e1-/- compared to Cyp2e+/+ mice. Microscopic alterations included bronchoalveolar adenomas, and in one Cyp2e1+/+ mouse treated with 100 mg/kg urethane, a bronchoalveolar carcinoma was diagnosed. Significant reduction in the incidence of adenomas and the number of adenomas/lung were observed in Cyp2e1-/- compared to Cyp2e1+/+ mice. In the Harderian gland, the incidences of hyperplasia and adenomas were significantly lower in Cyp2e1-/- compared to Cyp2e+/+ mice at the 10 mg/kg dose, with no significant differences observed at the high or low doses. In conclusion, this work demonstrated a significant reduction of urethane-induced carcinogenicity in Cyp2e1-/- compared to Cyp2e1+/+ mice and proved that CYP2E1-mediated oxidation plays an essential role in urethane-induced carcinogenicity.
氨基甲酸乙酯是一种已确定的动物致癌物，被归类为“合理预期为人类致癌物”。直到最近，通过酯酶进行的氨基甲酸乙酯代谢被认为是这种化学物质的主要代谢途径。然而，本实验室最近的研究表明，负责氨基甲酸乙酯氧化的主要酶是CYP2E1，而非酯酶。随后的研究表明，与Cyp2e1+/+小鼠相比，Cyp2e1-/-小鼠中氨基甲酸乙酯诱导的遗传毒性和细胞增殖受到显著抑制。利用Cyp2e1-/-小鼠，开展了当前的研究以评估氨基甲酸乙酯代谢与致癌性之间的关系。氨基甲酸乙酯以1、10或100mg/kg/天的剂量通过灌胃给药，每周5天，持续6周。动物在停止化学给药7个月后实施安乐死，并评估氨基甲酸乙酯的致癌性。显微镜检查显示，与Cyp2e+/+小鼠相比，Cyp2e1-/-小鼠肝脏血管瘤和血管肉瘤的发生率显著降低。肺结节呈剂量依赖性增加，与Cyp2e+/+小鼠相比，在Cyp2e1-/-小鼠中不太常见。显微镜下改变包括支气管肺泡腺瘤，在用100mg/kg氨基甲酸乙酯处理的一只Cyp2e1+/+小鼠中，诊断出了支气管肺泡癌。与Cyp2e1+/+小鼠相比，Cyp2e1-/-小鼠中腺瘤的发生率和腺瘤/肺的数量显著降低。在哈德氏腺中，与Cyp2e+/+小鼠相比，Cyp2e1-/-小鼠在10mg/kg剂量下增生和腺瘤的发生率显著较低，在高剂量或低剂量下未观察到显著差异。总之，这项研究表明，与Cyp2e1+/+小鼠相比，Cyp2e1-/-小鼠中氨基甲酸乙酯诱导的致癌性显著降低，并证明CYP2E1介导的氧化在氨基甲酸乙酯诱导的致癌性中起重要作用。
