Low Susceptibility of Long-Evans Cinnamon Rats to N-Butyl-N-(4-hydroxybutyl)-nitrosamine-induced Urinary Bladder Carcinogenesis and Inhibitory Effect of Urinary Copper

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Abstract
We studied the susceptibilities to N‐butyl‐N‐(4‐hydroxybutyl)nitrosamine (BBN)‐induced urinary bladder carcinogenesis of male Long‐Evans Cinnamon (LEC), F344 and Long‐Evans Agouti (LEA) rats. Male rats (n=21) were given 0.1% BBN in their drinking water from week 6, 8 and 10 for one week, and killed in week 56. The incidences of transitional cell tumors (papillomas plus carcinomas) in BBN‐treated LEC and F344 rats were 12% and 76%, respectively (P < 0.001, experiment 1), and those in LEC and LEA rats were 11% and 95%, respectively (P < 0.001, experiment 2). When male LEC and F344 rats were given 0.1% BBN in their drinking water for 7 days, the intake of BBN and the urinary concentration of its active metabolite, N‐butyl‐N‐(3‐carboxypropyl)nitrosamine (BCPN), were higher in the LEC rats (P < 0.01). The urinary pHs of untreated LEC and F344 rats were similar between week 6 and 30. The urinary copper concentration was lower in LEC rats before jaundice than in F344 rats, but its concentrations in 28‐ and 50‐week‐old LEC rats were 1.7 and 2.3 times those in F344 rats. In a two‐stage carcinogenesis study using F344 rats, i.p. injections of cupric nitrilotriacetate increased urinary copper excretion, and inhibited BBN induced bladder carcinogenesis. In a two‐stage carcinogenesis study using LEC rats, oral administration of D‐penicillamine decreased urinary copper excretion, and increased BBN‐induced bladder cancer, although the difference was not significant. These data show that LEC rats are resistant to bladder carcinogenesis and suggest that urinary copper has a significant role in their resistance.

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