Inhibition of gamma-glutamyl hydrolases in human cells by 2-mercaptomethylglutaric acid.

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.

authors

Whitehead VM,Kalman TI,Vuchich MJ

doi

10.1016/s0006-291x(87)80509-0

subject

Has Abstract

pub_date

1987-04-14 00:00:00

pages

292-7

issue

1

eissn

0006-291X

issn

1090-2104

pii

S0006-291X(87)80509-0

journal_volume

144

pub_type

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