Abstract:
:Cultured human lymphocytes and fibroblasts accumulate methotrexate during 24 hours and synthesize methotrexate polyglutamates up to the hexaglutamate, with the triglutamate predominating. In the interval after incubation with methotrexate, drug is lost, metabolites are converted to longer chain-lengths, and methotrexate pentaglutamate predominates. 2-Mercaptomethylglutaric acid, an inhibitor of neutral pH gamma-glutamyl hydrolases in vitro, had little effect on polyglutamate synthesis during incubation of the cells with methotrexate, but maintained for 48 hours almost all the methotrexate as the pentaglutamate when added after the removal of the drug. These findings demonstrate that inhibition of gamma-glutamyl hydrolases is an effective approach to alter the distribution of polyglutamate forms of methotrexate in vivo and indicate that enzymatic hydrolysis may contribute to regulation of polyglutamate chain lengths in human cells.
journal_name
Biochem Biophys Res Communjournal_title
Biochemical and biophysical research communicationsauthors
Whitehead VM,Kalman TI,Vuchich MJdoi
10.1016/s0006-291x(87)80509-0subject
Has Abstractpub_date
1987-04-14 00:00:00pages
292-7issue
1eissn
0006-291Xissn
1090-2104pii
S0006-291X(87)80509-0journal_volume
144pub_type
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