Inhibition of hereditary hepatitis and liver tumor development in Long-Evans cinnamon rats by the copper-chelating agent trientine dihydrochloride

Abstract

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.

Evolution of Exchangeable Copper and Relative Exchangeable Copper through the Course of Wilson's Disease in the Long Evans Cinnamon Rat

“…A copper profile in LEC rats includes reduction of serum level of copper, reduction of ceruloplasmin and ceruloplasmin oxidase activity (COA) and copper accumulation in the liver. In the majority of studies, an elevation of bilirubinemia and liver transaminases starts between 10 to 14 weeks of age, corresponding to the first acute liver failure episode [19], [20], [21].…”

Role of Atp7b Gene in Spontaneous and N‐Diethylnitrosamine‐induced Carcinogenesis in a New Congenic Strain, WKAH.C‐Atp7b Rats

“…In addition, copper chelating agents (D-penicillamine and trientine dihydrochloride) inhibited the development of liver tumors as well as hepatitis of LEC rats. [20][21][22] Iron-deficient diet also inhibits the development of liver tumors. 23) These data suggest that tumor development in LEC rats is a later event caused by chronic copper and/or iron toxicity.…”

Repeated transplantation of hepatocytes prevents fulminant hepatitis in a rat model of Wilson's disease

“…Blood was routinely taken throughout the observation period. The livers were inspected after sacrifice or resection (weeks [14][15][16].…”

“…8,11 The LEC rat is a well-characterized model for gene and cell-based therapy 12,13 and has many characteristics that are also observed in patients (eg, low ceruloplasmin levels, a sensitivity to anticopper therapy, and abnormal p53 expression). 8,10,[14][15][16] However, abnormal p53 expression is rare in humans, and most patients harbor missense mutations rather than deletions within ATP7B.…”