Mechanism of depletion of O6-methylguanine-DNA methyltransferase activity in rat tissues by O6-Benzyl-2'-deoxyguanosine. Role of metabolism.
O6-Benzyl-2'-deoxyguanosine (O6-BzldGuo) was found to be a potent inhibitor of O6-methylguanine-DNA methyltransferase (MGMT) activity in vivo, despite its demonstrated lower activity compared to O6-benzylguanine (O6-BzlGua) for inactivation of MGMT in cell cultures or cell free extracts. This difference is probably due to metabolism and possibly to enhanced systemic availability of O6-BzldGuo compared to O6-BzlGua in animals. At doses above 50 mg/kg, O6-BzldGuo completely suppresses the MGMT activity in liver, lung and brain for 12 to 18 hrs following treatment. However, it fails to suppress the activity in jejunum and possibly in other tissues with low blood perfusion rates. O6-BzldGuo is metabolized mainly in the liver, and possibly in kidney and lung, to yield the more potent MGMT inhibitors O6-BzlGua and O6-Benzyl-7,8-dihydro-8-oxoguanine (O6-Bzl(8-OX)Gua), that reach maximum levels following the decline of the parent compound both in tissues and the circulation. Although O6-BzldGuo may cause the initial drop of MGMT activity, continued prolonged suppression is likely due to the persistence of its MGMT-inhibiting metabolites. Severe suppression of MGMT activity and the presence of O6-BzldGuo and its metabolites in the brain indicates that this inhibitor crosses the blood-brain barrier. Prolonged suppression of MGMT in brain following a complete disappearance of the parent compound from the tissue also demonstrates the importance of metabolites in MGMT suppression. Such metabolites, especially O6-Bzl(8-OX)Gua, appear to accumulate in brain, possibly due to their hydrophobic nature. Accumulation of the parent compound in the pancreatic ducts may explain the unusual high concentrations of this compound in pancreas as compared to the spleen. Similarly, high concentrations of O6-BzldGuo in kidneys may be related to accumulation of the compound in proximal tubules and its poor reabsorption into the circulation. Overall, O6-BzldGuo shows tissue specificity which is modulated by dose. Such specificity seems to be related to accumulation of the parent compound in certain tissues, but more importantly, to site-specific metabolism and the persistence of MGMT inhibitory metabolites in these tissues. The combination of enhanced systemic availability and site specific metabolic activation and/or inactivation of O6-BzldGuo may be related to the enhanced antitumor therapeutic index against human tumor xenografts for this compound which equals or even exceeds that of O6-BzlGua.
Kokkinakis
D M
DM
Department of Neurology, University of Texas Southwestern Medical Center at Dallas 75235-9036, USA.
Moschel
R C
RC
Vuong
T H
TH
Reddy
M V
MV
Schold
S C
SC
Pegg
A E
AE
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007422:Intestines / Q000187:drug effects / Q000201:enzymology; D007668:Kidney / Q000187:drug effects / Q000201:enzymology; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008168:Lung / Q000187:drug effects / Q000201:enzymology; D008297:Male; D008780:Methyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019853:O(6)-Methylguanine-DNA Methyltransferase; D009928:Organ Specificity; D010179:Pancreas / Q000187:drug effects / Q000201:enzymology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013154:Spleen / Q000187:drug effects / Q000201:enzymology
D004791:Enzyme Inhibitors; C088636:O(6)-benzyl-2'-deoxyguanosine; D008780:Methyltransferases; D019853:O(6)-Methylguanine-DNA Methyltransferase; D003849:Deoxyguanosine