THE HIGH HEPATOCARCINOGEN SUSCEPTIBILITY OF LEC RATS IS GENETICALLY INDEPENDENT OF ABNORMAL COPPER ACCUMULATION IN THE LIVER

We previously reported that LEC rats, which show a spontaneous occurrence of liver injury and hepatocellular carcinoma (HCC), are highly susceptible to chemical carcinogens such as diethylnitrosamine (DEN). Since abnormal copper accumulation in the liver of LEC rats was found to be a cause of liver injury, it is necessary to elucidate whether the carcinogen susceptibility of LEC rats is related to the accumulation of copper in the liver. In this study we have examined the relationship between the susceptibility of F1 [LECxLEA or LECxFischer 344 (F344)] and F1 backcross rats to DEN and hepatic copper concentration, as copper accumulation has been demonstrated to be inherited as an autosomal recessive trait. The groups of F1 and F1 backcross rats were given a single intraperitoneal injection of DEN (20 mg/kg body wt) and subjected to a modified Solt-Farber protocol for assaying glutathione S-transferase placental form (GST-P)-positive foci, The hepatic copper concentration was examined by atomic absorption. Although no F1 rats showed a high copper concentration in the liver the numbers of foci were as high as those in LEC rats which accumulate copper, Backcross rats separated into high and low copper concentration groups at an almost 1:1 ratio, but there was no significant difference in the mean numbers of foci between these two groups. The results clearly indicate that the high susceptibility of LEC rats to DEN is genetically independent of copper accumulation in the liver A possible dominant inheritance of this high carcinogen susceptibility was suggested, Biochemical measurement of cytochromes P450 and b5 in the liver of F1 rats indicated that alterations in drug metabolizing enzymes may be partially responsible for the high carcinogen susceptibility of LEC rats.