This project deals with the bioorganic chemistry underlying tumor induction by the environmental carcinogens dimethylnitrosamine, diethylnitrosamine and related compounds. The steric course of the transfer of the methyl group, made chiral by incorporating the three hydrogen isotopes, H, D, and T in an asymmetric arrangement, from four carcinogenic methylating agents, mehtyl methanesulfonate, methyl nitrosourea, dimethylnitrosamine and N-methyl-N-(Alpha-acetoxymethyl)nitrosamine, to model necleophiles in vitro and to various sites on DNA in vitro and in vivo will be studied. The results will indicate whether the stereochemical mechanism is the same in vivo as in vitro (suggesting that the reaction environment is similar), whether it is the same for different sites on the DNA (suggesting that the nature of the nucelophile has little influence on the mechanism) and whether it is the same in different tissues and animal species (suggesting that the biological system as a whole has little influence on the mechanism). Opposite results would, of course, lead to opposite conclusions. In addition the results will show whether the stereochemical fate of the methyl diazonium ion, an ultimate carcinogen, generated in three different ways in the cell, is the same in each case. Tumor induction shows a deuterium isotope effect when the carcinogenic potency of perdeuterated and unlabeled dimethylnitrosamine is compared. We will measure the deuterium isotope effect in the metabolism of [1-2H2]diethylnitrosamine leading to the transfer of ethyl groups to DNA in order to determine whether all the ethyl groups at different sites in DNA come from the same pool of activated species, whether DNA alkylation in different tissues of an animal draws on the same pool of activated species, and which P450 enzymes are most prominently involved in diethylnitrosamine activation in vivo. We will also determine the steric preference between HP and HS at C-1 in diethylnitrosamine activation in vitro and whether this preference varies for different P450 enzymes. The results will establish whether this parameter can also be used to characterize the involvement of particular P450 enzymes in diethylnitrosamine activation in vivo.
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| Epstein, J; Xiao, H Q; Oba, B K (1989) P-glycoprotein expression in plasma-cell myeloma is associated with resistance to VAD. Blood 74:913-7 |
