Effect of route of administration of environmental methylating agents on 7-methylguanine formation in white blood cells and internal organs: implications for molecular epidemiology.
The measurement of 7-methylguanine (7-meG) in white blood cells (WBC) is a promising biomarker of individual human exposure to environmental methylating agents. To test the validity of using WBC as a surrogate dosimeter for internal tissues, levels of 7-meG were measured in rat WBC, liver and target organs for carcinogenesis 16 h after oral administration of several methylating carcinogens (DMN, DMH, NNK, NMBA). 7-MeG was detected in WBC DNA but levels were far lower than in internal organs. While the ratio between 7-meG formation in target organs and WBC was highly variable depending on the carcinogen administered, the ratio between 7-meG in the liver and WBC was in the same order of magnitude for each carcinogen, ranging from 81 to 143. In addition, levels of 7-meG in the liver and WBC within individual animals were highly correlated (r = 0.94, P < 0.0001). These results confirmed our previous observations with the same carcinogens after intraperitoneal injection. In order to assess if the lower level of 7-meG in WBC was a result of a low metabolism of methylating agents in WBC, microsomes were prepared from control rat lymphocytes and DMN demethylase activity was measured. The total amount of microsomal proteins was extremely low, especially in comparison with hepatic cells, and the enzymatic activity was less than 0.48 nmol HCHO/min/mg protein, while an activity of 1.26 nmol HCHO/min/mg protein was measured in liver microsomes. Taken together, these results suggest that the presence of 7-meG in WBC DNA reflects an exposure to methylating agents; the level of 7-meG in WBC seems predictive of the level of adduct in the liver, possibly because active methylating species are formed in the liver and then transferred into the hepatic circulation, where the WBC are exposed. It is now important to examine this relationship in humans where exposures are generally to lower levels of carcinogens over long time periods.
Bianchini
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International Agency for Research on Cancer, Lyon, France.
Wild
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CP
D000284:Administration, Oral; D000477:Alkylating Agents / Q000008:administration & dosage*; D000818:Animals; D002274:Carcinogens, Environmental / Q000008:administration & dosage*; D019392:Cytochrome P-450 CYP2E1; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D018736:DNA Adducts / Q000378:metabolism; D006147:Guanine / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000097:blood; D007274:Injections, Intraperitoneal; D007962:Leukocytes / Q000378:metabolism*; D008099:Liver; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D009602:Nitrosamines / Q000378:metabolism; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism; D051381:Rats
D000477:Alkylating Agents; D002274:Carcinogens, Environmental; D018736:DNA Adducts; D009602:Nitrosamines; D006147:Guanine; C008450:7-methylguanine; D003577:Cytochrome P-450 Enzyme System; D019392:Cytochrome P-450 CYP2E1; D010089:Oxidoreductases, N-Demethylating