Glutathione depletion-induced thymidylate insufficiency for DNA repair synthesis.
Dietary methionine (Met) deficiency is known to divert folate away from de novo biosyntheses of purines and the pyrimidine, thymidylate, to the resynthesis of Met resulting in deoxynucleoside triphosphate imbalance. We have recently shown that Met can easily be depleted and methylation can be impaired by exposure to a model glutathione (GSH)-depleting agent, bromobenzene (BB). GSH depletion-induced Met depletion, therefore, 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 interesting results were found. The administration of Thy labeled with [2-14C]Thy to BB-treated Syrian hamsters at either 1, 5, 7 or 9 h after BB resulted in an attenuation of liver toxicity. Intrahepatic hemorrhage, which is a typical characteristic of BB toxicity in the Syrian hamster, was decreased in the BB + Thy groups. The attenuation of liver toxicity was accompanied by a progressive increase of Thy incorporation into liver genomic DNA at 24 h after BB. With respect to the time points chosen for Thy administration, Thy incorporation found in the BB + Thy groups were 2-, 2-, 3- and 4-fold of the controls that received only Thy. The results provide evidence that BB causes a progressive increase of thymidylate insufficiency in liver cells. Thymidylate insufficiency is due to Met depletion, a depletion that occurs as a result of GSH depletion.
Lertratanangkoon
K
K
Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Galveston 77555-1031, USA. klertrat@mspo3.med.utmb.edu
Savaraj
N
N
Scimeca
J M
JM
Thomas
M L
ML
D000818:Animals; D001969:Bromobenzenes / Q000633:toxicity; D006224:Cricetinae; D004247:DNA / Q000096:biosynthesis*; D004260:DNA Repair; D005978:Glutathione / Q000172:deficiency* / Q000378:metabolism*; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008647:Mesocricetus; D008715:Methionine / Q000096:biosynthesis / Q000172:deficiency; D013938:Thymidine Monophosphate / Q000172:deficiency* / Q000378:metabolism*
D001969:Bromobenzenes; D013938:Thymidine Monophosphate; D004247:DNA; D008715:Methionine; C032036:bromobenzene; D005978:Glutathione