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

Abstract

long-term administration of the agent. The copper level Trientine dihydrochloride (trientine) is an alternative in the liver of treated rats was reduced by 33% at 87 medicinal copper chelating agent for patients with Wilweeks of age. Development of HCC in LEC rats might be son's disease of penicillamine intolerance. We examined partly, but not totally, because of copper accumulation. the effects of trientine on the spontaneous development No effects on the levels of copper, iron, or zinc in the of hepatitis and hepatic tumors, by its short-term and liver of LEA rats was detected, and no adverse effects long-term administration to Long-Evans cinnamon were detected in either LEC or LEA rats after both short-(LEC) rats with an accumulation of copper in the liver, and long-term administration of trientine in drinking as animal models of Wilson's disease. Male rats were water. (HEPATOLOGY 1996;23:764-770.) 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 ppmThe mutant strain of rats, LEC (Long-Evans cinnafor 52 weeks, from 8 to 87 weeks of age in the long-term mon) was first found after sudden death of a number experiment. Development of hepatitis was observed in the control LEC rats at 18 weeks of age. They had high of them at 18-20 weeks of age, following their developlevels of plasma transaminases (glutamic oxaloacetic ment of hepatitis. This strain of rats consistently develtransaminase [GOT], glutamic pyruvic transaminase ops hepatitis with varying degrees of severity. The hep-[GPT]), and on pathological examination, hepatocyte de-atitis is characterized by an increase in the serum struction was observed. Histological findings revealed levels of glutamic oxaloacetic transaminase (GOT) and that short-term administration of trientine inhibited the glutamic pyruvic transaminase (GPT), hyperbilirubidevelopment of hepatitis remarkably. The plasma GOT nemia, and massive necrosis without an inflammatory and GPT levels of treated animals were only slightly cells response. [1][2][3] Most of the rats surviving the hepati- In the long-term administration of trientine, the inci-accumulate copper in their livers. 5 By linkage analysis dence of hepatic cell carcinoma (HCC) in the treated rats of F 1 back-crosses, we found that the genetic trait leadwas 67% that of the untreated LEC rats, and the number ing to the accumulation of copper in the liver is tightly of HCCs per rat in the treated group was 0.7 { 0.5, being linked with development of hepatitis. 6 Linkage analysignificantly lower as compared with 4.7 { 3.5 in the sis of F 1 back-crosses has also suggested that the gene untreated rats. Additionally, the development of cholan-responsible for Wilson's disease (Wc1/pWD), which engiofibrosis in LEC rats was completely prevented by codes a copper transporting P-type ATPase (ATP7B), is a candidate gene for hepatitis development in LEC rats. 7,8 Actually, a deletion in the rat Atp7b was found. 9Abbreviations: LEC, Lon...

L‐carnitine inhibits hepatocarcinogenesis via protection of mitochondria

“…Excessive accumulated copper is considered to be responsible for the hepatocarcinogenesis observed in LEC rats. 34 It is now well known that excess heavy metals, such as copper and iron, generate ROS such as superoxide anion and hydrogen peroxide, catalyzing the formation of highly toxic hydroxyl radicals via a Fenton-like reaction. 35 Hydroxyl radicals can then initiate lipid peroxidation chain reactions, thereby disrupting cellular membranes, mainly mitochondrial membranes, 36,37 and damage the DNA of both the mitochondria and nucleus.…”

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.…”

Role of Copper Accumulation in Spontaneous Renal Carcinogenesis in Long‐Evans Cinnamon Rats

“…8) The reason for this is unknown, but the decrease of hepatic copper concentration by chelating agents may increase intestinal iron absorption or iron uptake into hepatocytes. 35) Lesions such as altered tubules 36) and atypical tubules and hyperplasia 37) are known as renal preneoplastic lesions in rodents.…”

“…7,8) Patients with Wilson's disease are known to have abnormal renal function and penicillamine therapy improves their renal function, 9) but we know of no reports of renal neoplasms in cases of Wilson's disease. We have reported that renal cell tumors develop spontaneously in LEC rats.…”

“…[4][5][6] Both the hepatitis and hepatocellular carcinomas can be prevented by treatment with the copper-chelating agent, D-penicillamine or trientine. 7,8) Patients with Wilson's disease are known to have abnormal renal function and penicillamine therapy improves their renal function, 9) but we know of no reports of renal neoplasms in cases of Wilson's disease. We have reported that renal cell tumors develop spontaneously in LEC rats.…”