Carcinogenesis, Vol 18, 287-293, Copyright © 1997 by Oxford University Press
SJ James, BJ Miller, AG Basnakian, IP Pogribny, M Pogribna and L Muskhelishvili
Weanling male F344 rats were fed either a semi-purified diet low in
methionine and lacking in choline and folic acid (folate/methyl deficient)
or a supplemented control diet for periods of 2, 5, 7 days, 3 weeks, and 9
weeks. Two days after initiating the folate/methyl deficient diet in
weanling F344 rats, the incidence of apoptotic bodies, identified by in
situ end-labeling of 3'-OH DNA strand breaks, was significantly increased
in liver sections from the deficient rats. Apoptotic cell death was
confirmed biochemically by an increase in nuclear Ca2+/Mg2+-dependent
endonuclease activity that paralleled the increase in apoptotic bodies over
the 9-week feeding period. There was no morphologic evidence of necrotic
foci or necrosis-associated inflammatory response over the 9-week period.
Confirming that cell turnover is chronically elevated in this model, the
increase in apoptotic rate was accompanied by a sustained increase in the
mitotic index (MI). The DNA repair-associated enzyme, poly(ADPribose)
polymerase (PARP), was similarly elevated and was associated with
significant decreases in the substrate for ADPribose polymer synthesis,
nicotinamide adenine dinucleotide (NAD). Because folate metabolites are
essential for de novo purine and thymidine biosynthesis, prolonged
deficiency in folic acid can induce an imbalance in the deoxynucleotide
precursors for DNA replication/repair and negatively affect the fidelity of
DNA synthesis. Using an HPLC method, hepatic deoxyuridine triphosphate
(dUTP) levels were increased at 3 and 9 weeks after initiation of the
deficient diet and levels of thymidine triphosphate (dTTP) were reduced. An
increase in dUTP/ dTTP ratio is consistent with a block in folate-dependent
de novo thymidylate biosynthesis and may predispose to uracil
misincorporation and DNA repair-related DNA strand breaks.
ARTICLES
Apoptosis and proliferation under conditions of deoxynucleotide pool imbalance in liver of folate/methyl deficient rats
Division of Nutritional Toxicology, National Center for Toxicological Research, Jefferson, AR 72079, USA.
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