Cytochrome P‐450 Isozyme Pattern Is Related to Individual Susceptibility to Diethylnitrosamine‐induced Liver Cancer in Rats

摘要

Differences in susceptibility to chemical carcinogenesis between rodent strains and species have been linked to variations in genetically‐determined mixed function oxidase activities. In order to verify whether such variations also determine the susceptibility of individual animals of the same strain to a chemical carcinogen, outbred male Wistar rats were administered diethylnitrosamine (DEN) (1, 2, or 3 nig/kg) five times a week for 20 weeks. The relationship was examined between the outcome (i.e. presence or absence of liver tumors, and latency period) and the hepatic activities of mixed function oxidases and conjugating enzymes, as well as of O⁶‐methylguanine‐DNA‐methyltransferase, measured before the carcinogen treatment. In addition, the metabolic profiles of two model drugs, antipyrine and disopyramide, in the urine were analyzed and correlated with the carcinogen susceptibility. The length of the latency period of hepatocellular tumors in individual rats was negatively related to the activities of hepatic dimethylnitrosamine N‐demethylase, aryl hydrocarbon hydroxylase and epoxide hydrolase and positively related to the amount of microsomal protein. Consistent relationships between the other 10 measured parameters and the susceptibility to DEN‐induced carcinogenesis were not detected. Long‐term treatment with DEN slightly decreased the proportion of metabolism of antipyrine into norantipyrine, and increased the share of 4‐hydroxyantipyrine; a decrease in the metabolism of disopyramide to N‐deisopropyldisopyramide was also detected. It is concluded that the pattern of cytochrome P‐450 isoenzymes is related to differences in individual susceptibility to nitrosamineinduced carcinogenesis. The relationship was most marked at low dose levels, which are the levels at which nitrosamine exposures of humans are known to occur.