EFFECT OF ROUTE OF ADMINISTRATION OF ENVIRONMENTAL METHYLATING AGENTSON 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 W BC, liver and target organs for carcinogenesis 16 h after oral adminis tration of several methylating carcinogens (DMN, DMH, NNK, NMBA). 7-Me G was detected in WBC DNA but levels were far lower than in internal o rgans. While the ratio between 7-meG formation in target organs and WB C was highly variable depending on the carcinogen administered, the ra tio between 7-meG in the liver and WBC was in the same order of magnit ude for each carcinogen, ranging from 81 to 143. In addition, levels o f 7-meG in the liver and WBC within individual animals were highly cor related (r = 0.94, P < 0.0001). These results confirmed our previous o bservations 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 prepar ed from,control rat lymphocytes and DMN demethylase activity was measu red. The total amount of microsomal proteins was extremely low, especi ally 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 nmo l 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 pr edictive 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 importan t to examine this relationship in humans where exposures are generally to lower levels of carcinogens over long time periods.