Document Detail


Debenzylation of O(6)-benzyl-8-oxoguanine in human liver: implications for O(6)-benzylguanine metabolism.
MedLine Citation:
PMID:  11266657     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
O(6)-Benzylguanine (BG) effectively inactivates the DNA repair protein O(6)-alkylguanine-DNA alkyltransferase, and enhances the effectiveness of 1,3-bis(2-chloroethyl)-1-nitrosourea in cells in culture and tumor-bearing animals. BG is presently in phase II clinical trials. In humans, BG is converted to O(6)-benzyl-8-oxoguanine (8-oxoBG), a longer-lived, yet equally potent inactivator. We have isolated and identified the debenzylated product, 8-oxoguanine, in plasma and urine of patients following administration of BG. The purpose of this work was to determine the human liver enzymes responsible for the debenzylation of 8-oxoBG. Therefore, 8-oxoBG was incubated with human liver microsomes and cytosol, and the concentration of 8-oxoguanine was determined. No appreciable product was formed in the cytosol; however, increasing amounts of 8-oxoguanine were formed with increasing concentrations of pooled human liver microsomes. The amount of 8-oxoguanine formed increased with time and substrate concentration. Co-incubation of human liver microsomes with 8-oxoBG and various cytochrome P450 isoform-selective inhibitors suggested the possible involvement of CYP1A2, 2E1, and/or 2A6 in this reaction. Incubation of 8-oxoBG with baculovirus cDNA-overexpressed CYP1A2, 2E1, 2A6, and 3A4 demonstrated that formation of 8-oxoguanine was due mainly to CYP1A2. Debenzylation of 8-oxoBG complied with Michaelis-Menten kinetics with K(m) and V(max) values of 35.9 microM and 0.59 pmol/min/pmol of CYP1A2, respectively. CYP1A2 appears to be mainly responsible for the debenzylation of 8-oxoBG in human liver.
Authors:
L Long; R C Moschel; M E Dolan
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Biochemical pharmacology     Volume:  61     ISSN:  0006-2952     ISO Abbreviation:  Biochem. Pharmacol.     Publication Date:  2001 Mar 
Date Detail:
Created Date:  2001-03-27     Completed Date:  2001-04-19     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  0101032     Medline TA:  Biochem Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  721-6     Citation Subset:  IM    
Affiliation:
Section of Hematology-Oncology, Department of Medicine and Cancer Research Center, Committee on Clinical Pharmacology, University of Chicago, IL 60637, USA.
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MeSH Terms
Descriptor/Qualifier:
Cytochrome P-450 CYP1A2 / genetics,  metabolism*
DNA, Complementary / genetics
Guanine / analogs & derivatives*,  metabolism*
Humans
Isoenzymes / genetics,  metabolism
Liver / enzymology,  metabolism*
Grant Support
ID/Acronym/Agency:
CA57725/CA/NCI NIH HHS; CA71627/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/DNA, Complementary; 0/Isoenzymes; 0/O(6)-benzyl-8-oxoguanine; 19916-73-5/O(6)-benzylguanine; 5614-64-2/8-hydroxyguanine; 73-40-5/Guanine; EC 1.14.14.1/Cytochrome P-450 CYP1A2

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