Sone K, Maeda M, Wakabayashi K, Takeichi N, Mori M, Sugimura T, Nagao M
Carcinogenesis Division, National Cancer Center Research Institute, Tokyo, Japan.
Hepatology. 1996 Apr;23(4):764-70. doi: 10.1053/jhep.1996.v23.pm0008666330.
Trientine dihydrochloride (trientine) is an alternative medicinal copper chelating agent for patients with Wilson's disease of penicillamine intolerance. We examined the effects of trientine on the spontaneous development of hepatitis and hepatic tumors, by its short-term and long-term administration to Long-Evans cinnamon (LEC) rats with an accumulation of copper in the liver, as animal models of Wilson's disease. Male rats were given trientine in their drinking water at 1500 ppm for 18 weeks, from 6 weeks to 24 weeks of age in short-term experiment, and 1500 ppm for 27 weeks then 750 ppm for 52 weeks, from 8 to 87 weeks of age in the long-term experiment. Development of hepatitis was observed in the control LEC rats at 18 weeks of age. They had high levels of plasma transaminases (glutamic oxaloacetic transaminase [GOT], glutamic pyruvic transaminase [GPT]), and on pathological examination, hepatocyte destruction was observed. Histological findings revealed that short-term administration of trientine inhibited the development of hepatitis remarkably. The plasma GOT and GPT levels of treated animals were only slightly higher than those of normal LEA (Long-Evans with agouti coat color) rats, a sibling line of LEC rats. Copper levels in the liver were decreased by a maximum of 50 percent. In the long-term administration of trientine, the incidence of hepatic cell carcinoma (HCC) in the treated rats was 67 percent that of the untreated LEC rats, and the number of HCCs per rat in the treated group was 0.7 +/- 0.5, being significantly lower as compared with 4.7 +/- 3.5 in the untreated rats. Additionally, the development of cholangiofibrosis in LEC rats was completely prevented by long-term administration of the agent. The copper level in the liver of treated rats was reduced by 33 percent at 87 weeks of age. Development of HCC in LEC rats might be partly, but not totally, because of copper accumulation. No effects on the levels of copper, iron, or zinc in the liver of LEA rats was detected, and no adverse effects were detected in either LEC or LEA rats after both short- and long-term administration of trientine in drinking water.
二盐酸曲恩汀是一种可供对青霉胺不耐受的威尔逊病患者使用的替代性医用铜螯合剂。我们通过对肝脏中铜蓄积的长-伊文斯肉桂色（LEC）大鼠短期和长期给予二盐酸曲恩汀，来研究其对肝炎和肝肿瘤自发发展的影响，这些大鼠作为威尔逊病的动物模型。在短期实验中，雄性大鼠从6周龄至24周龄期间，饮用含1500 ppm二盐酸曲恩汀的水18周；在长期实验中，雄性大鼠从8周龄至87周龄期间，先饮用含1500 ppm二盐酸曲恩汀的水27周，然后饮用含750 ppm二盐酸曲恩汀的水52周。在18周龄时，对照LEC大鼠出现了肝炎。它们的血浆转氨酶（谷草转氨酶[GOT]、谷丙转氨酶[GPT]）水平很高，并且在病理检查中观察到肝细胞破坏。组织学结果显示，短期给予二盐酸曲恩汀可显著抑制肝炎的发展。接受治疗的动物的血浆GOT和GPT水平仅略高于正常LEA（带刺豚鼠毛色的长-伊文斯）大鼠，LEA大鼠是LEC大鼠的同窝品系。肝脏中的铜水平最多降低了50%。在长期给予二盐酸曲恩汀的实验中，接受治疗的大鼠肝细胞癌（HCC）的发生率为未治疗LEC大鼠的67%，并且治疗组每只大鼠的HCC数量为0.7±0.5，与未治疗大鼠的4.7±3.5相比显著更低。此外，长期给予该药物可完全预防LEC大鼠胆管纤维化的发展。在87周龄时，接受治疗的大鼠肝脏中的铜水平降低了33%。LEC大鼠中HCC的发展可能部分（但不是全部）是由于铜蓄积。未检测到二盐酸曲恩汀对LEA大鼠肝脏中的铜、铁或锌水平有影响，并且在饮用水中短期和长期给予二盐酸曲恩汀后，在LEC或LEA大鼠中均未检测到不良反应。
