ALKYLATION &MUTAGENESIS BY PANCREAS CARCINOGENS

N-Nitrosobis(2-oxopropyl)amine (BOP), at a dose of 10 mg/kg, has
induced only pancreatic ductular adenocarcinoma (PDA) in
hamsters. BOP methylated liver and pancreas DNA and also 2-
hydroxypropylated liver DNA. In this proposal, we will compare
the roles of methylation and 2-hydroxypropylation in BOP-induced
mutagenicity in V79 cells and by analogy, BOP-induced
carcinogenicity. This will be done by using two direct-acting
compounds, which each mimic one of the alkylating species
generated by BOP Ethyl-N-nitroso(2-oxopropyl)amine (NOPC) (a
methylating agent) and the 2-hydroxypropyl analog (NHPC) (a 2-
hydroxypropylating agent). Their mutagenicity in the V79 assay
will be measured and compared with the alkylation of V79 DNA,
which each produces. In both studies, a range of doses will be
used. This work could indicate whether alkylation at the 0-4
position of thymine or the 0-6 position of guanine is the crucial
site for BOP carcinogenicity. The major aim of this phase of the
study is to compare, and it is hoped, to determine the relative
roles of methylation and 2-hydroxypropylation in BOP
carcinogenesis. Because of the excellent correlation between
BOP carcinogenicity and its mutagenicity in the V79 assay,
mutagenicity will be used in lieu of carcinogenicity in this study.
The second phase is to determine the target cells BOP in the
pancreas, using isolated pancreas acinar and duct cells. Their
ability to activate BOP to mutagenic metabolites will be
measured when the cells are co-cultivated with the V79 cells.
The persistence of alkylation, particularly of 0-4-thymine and 0-
6-guanine will be measured in two circumstances. In the first, the
pancreas cells will be incubated with BOP, NOPC and NHPC in
vitro. The extent and persistence of alkylation will be measured
in cultured cells. In the second, the alkylation of pancreas cell
DNA will be measured in hamsters given BOP in vivo.