K. Lertratanangkoon et al., GLUTATHIONE DEPLETION-INDUCED THYMIDYLATE INSUFFICIENCY FOR DNA-REPAIR SYNTHESIS, Biochemical and biophysical research communications, 234(2), 1997, pp. 470-475
Dietary methionine (Met) deficiency is known to divert folate away fro
m de novo biosyntheses of purines and the pyrimidine, thymidylate, to
the resynthesis of Met resulting in deoxynucleoside triphosphate imbal
ance. We have recently shown that Met can easily be depleted and methy
lation can be impaired by exposure to a model glutathione (GSH)-deplet
ing agent, bromobenzene (BE). GSH depletion-induced Met depletion, the
refore, could cause thymidylate insufficiency for DNA repair synthesis
. The administration of thymidine (Thy) should repair this impairment.
When this hypothesis was examined in the present study, several inter
esting results were found. The administration of Thy labeled with [2-C
-14]Thy to BB-treated Syrian hamsters at either 1, 5, 7 or 9 h after B
B resulted in an attenuation of liver toxicity. Intrahepatic hemorrhag
e, which is a typical characteristic of BE toxicity in the Syrian hams
ter, was decreased in the BE + Thy groups. The attenuation of liver to
xicity was accompanied by a progressive increase of Thy incorporation
into liver genomic DNA at 24 h after BE. With respect to the time poin
ts chosen for Thy administration, Thy incorporation found in the BE Thy groups were 2-, 2-, 3- and 4-fold of the controls that received on
ly Thy. The results provide evidence that BE causes a progressive incr
ease of thymidylate insufficiency in liver cells. Thymidylate insuffic
iency is due to Met depletion, a depletion that occurs as a result of
GSH depletion. (C) 1997 Academic Press.