Alkylation of cellular macromolecules and target specificity of carcinogenic nitrosodialkylamines: metabolic activation by cytochromes P450 2B1 and 2E1 |
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Authors: | Shu L; Hollenberg PF |
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Institution: | Department of Pharmacology, The University of Michigan, Ann Arbor 48109- 0634, USA. |
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Abstract: | The alkylation of DNA, RNA and protein by labeled metabolites of alpha-
14C]nitrosodimethylamine (NDMA), alpha-14C]nitrosodipropylamine (NDPA) and
alpha-14C]nitrosodibutylamine (NDBA) was determined as a measure of the
metabolic activation of these nitrosamine carcinogens in vitro using
microsomes prepared from freshly isolated rat hepatocytes as well as in
intact cells using primary cultured rat hepatocytes. The abilities of these
nitrosodialkylamines to alkylate cellular macromolecules were significantly
affected by pretreatment of rats with inducers of cytochrome P450 and were
related to the specific activities of cytochrome P450 2B1 or 2E1 in rat
hepatocytes. Pretreatment of rats with phenobarbital (PB) substantially
increased the catalytic activity of pentoxyresorufin (PR) O-depentylase, an
activity catalyzed by cytochrome P450 2B1, in rat hepatocytes. The increase
in the PR O- depentylase activity was associated with a significant
increase in the alkylation of DNA or RNA by NDPA, and in alkylation by
NDBA, particularly of proteins. However, induction of cytochrome P450 2B1
resulted in a significant decrease in alkylation of cellular macromolecules
by NDMA in all cases. In contrast, enhancement of the catalytic activity of
the p-nitrophenol (pNP) hydroxylase (P450 2E1) due to pretreatment of rats
with pyridine (PYR) resulted in a significant increase in the alkylation of
cellular DNA by NDMA. The induction of cytochrome P450 2E1 also increased
the alkylation of DNA and RNA by NDPA, but to a lesser extent. Inhibition
studies using the chemical inhibitors orphenadrine (OP) and
diethyldithiocarbamate (DDC), which are specific for cytochromes P450 2B1
and 2E1, respectively, indicated that cytochrome P450 2B1 was not involved
in the metabolic activation of NDMA and that cytochrome P450 2E1 was not
responsible for the bioactivation of NDBA. The results presented here
demonstrate the substrate specificity and important role of cytochromes
P450 2B1 and 2E1 in the bioactivation of nitrosodialkylamines, and suggest
that multiple mechanisms may be involved in carcinogenesis induced by
nitrosodialkylamines.
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