CIRCADIAN VARIATION IN O-6-METHYLGUANINE-DNA METHYLTRANSFERASE ACTIVITY IN MOUSE-LIVER

Bifunctional chloroethylating cytostatic agents produce lethal DNA les ions, as a result of the formation of O-6-alkylguanines. These lesions can be repaired by O-6-methylguanine-DNA methyltransferase (MGMT), Th is ubiquitous nuclear and cytosolic enzyme removes the alkyl group by accepting it to the cysteine residue of its active site, thus preventi ng the formation of DNA interstrand cross-links, The role of the circa dian organization in cellular protection against such DNA insults was examined in male B6D2F1 mice, synchronized with an alternation of 12 h of light and 12 h of darkness (LD12:12). MGMT activity was determined in liver of mice obtained at eight different circadian times, located 3 h apart, MGMT activity varied B-fold along the 24 h time-scale, fro m 7 +/- 1 pmol/g of tissue at 7 h after light onset (HALO), during the rest span, up to 32 +/- 9 pmol/g at 19 HALO (second mid to late activ ity span). This large amplitude circadian rhythm in MGMT activity may be an important determinant of the susceptibility rhythms to alkylatin g agents, The greatest DNA repair activity occured at night when mice were active, eat and drink, and thus are at a higher risk of being exp osed to chemical insults.