| ABSTRACT: |
|
Approximately one third of all cancer deaths in the United States can
be linked to the use of tobacco products. Cessation of smoking is not
always an effective prevention method, especially since nicotine is so
addictive. For those individuals who continue to use tobacco products,
chemoprevention may be an alternative to reduce their cancer risk. We have
investigated the chemopreventive efficacy of five phenolic (catechin,
ellagic acid, esculetin, esculin, and propyl gallate) and five
non-phenolic (capsaicin, silymarin, diallyl sulfide, tannic acid, and
d-limonene) phytochemicals on tobacco-specific nitrosamine (NNK)-induced
mutagenesis and NNK metabolism. In the mutagenesis studies, Salmonella
typhimurium strain TA1535 was used in the Ames/mammalian
microsome/mutagenesis assay. In the initial studies, we determined that
the optimal conditions for NNK-induced mutagenesis included the use of
master plates and agar plates that were less than one week old, saline as
a solvent for NNK, 1 mg hamster liver microsomal protein, and minimal
DMSO. Experimental results showed that NNK-induced mutagenesis and
metabolism of NNK was enhanced by microsomes from both phenobarbital (PB)
and beta-naphthoflavone (beta-NF) treated hamsters and that the effect of
the phenolic compounds on NNK-induced mutagenesis depended upon treatment.
Ellagic acid was the most efficient inhibitor of NNK-induced mutagenesis
by microsomes from untreated animals (controls) while propyl gallate was
the most effective inhibitor of mutagenesis by microsomes from PB and
beta-NF treated animals. The effect of the phenolic compounds on the
microsome-mediated metabolism of NNK correlated with the effect on
mutagenesis to some extent. Capsaicin and tannic acid were the most potent
inhibitors of NNK-induced mutagenesis of the non-phenolic phytochemicals.
Diallyl sulfide was weakly antimutagenic and d-limonene and silymarin had
no effect All five non-phenolic compounds inhibited the alpha-carbon
hydroxylation pathway of NNK metabolism. Studies of the effect of
capsaicin on NNK metabolism by microsomes from untreated, PB-treated and
beta-NF-treated animals showed that capsaicin inhibited the formation of
all metabolites of NNK by all microsomal fractions. (Full text available
from University Microfilms International, Ann Arbor, MI, as Order No.
AAD94-28315) |