Inactivation of O6-alkylguanine-DNA alkyltransferase in the rat liver due to an intraperitoneal administration of methylated DNA.
Intraperitoneal administration of 6.5 mg of in vitro methylated DNA (meDNA) containing 1.5 x 10(-4) mM of O6-methylguanine (6MG) to male outbred rats weighing 150 g led to a considerable decrease in the activity of liver O6-alkylguanine-DNA alkyltransferase (AT). One hour after treatment there occurred a 4- to 5-fold decrease in the AT activity followed by its slow recovery. However, after 48 h, AT activity considerably exceeded control levels. A 5-fold decrease in the amount of administered meDNA resulted in the absence of its effect, whereas administration of higher amounts produced a further AT inactivation. A similar treatment with non-methylated DNA did not change AT activity. The possibility of AT exhaustion under in vivo conditions and thereby inhibition of repair of O6-alkylguanine in DNA, playing a key role in mutagenic, carcinogenic and antineoplastic effects of certain alkylating agents, might be helpful in increasing susceptibility of animals to such compounds.
Likhachev
A
A
N.N.Petrov Research Institute of Oncology, Leningrad, USSR.
Anisimov
V
V
Zhukovskaya
N
N
Petrov
A
A
D000818:Animals; D004247:DNA / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006147:Guanine / Q000031:analogs & derivatives; D008099:Liver / Q000201:enzymology; D008745:Methylation; D008780:Methyltransferases / Q000037:antagonists & inhibitors*; D019853:O(6)-Methylguanine-DNA Methyltransferase; D051381:Rats; D013329:Structure-Activity Relationship
D006147:Guanine; D004247:DNA; C008449:O-(6)-methylguanine; D008780:Methyltransferases; D019853:O(6)-Methylguanine-DNA Methyltransferase