Abstract：
:Glutathione S-transferases (GSTs) are important as drug metabolizing enzymes mainly in the detoxication process. To assess individual differences in susceptibility to different chemicals, it would be useful to know the activity of specific GST isozymes in individuals. In order to study individual variability, typical substrates specific for the three major classes of GSTs were used not only as substrates but also as inhibitors using 17 organ-donor livers. Out of 17, 4 livers were low in the mu-form isozyme, judging from the depressed GST activity for trans-4-phenyl-3-buten-2-one (tPBO), a mu-class substrate. The range of tPBO activity exhibited more than 20-fold variation, while less than 2-fold variation was observed in the activities for 1-chloro-2,4-dinitrobenzene (CDNB), a non-specific substrate for alpha-, mu-, and pi-class GSTs. In addition to the conventional approach to assessing individual variability, well known substrates for GSTs, cumene hydroperoxide (CHP, alpha-class), tPBO (mu) and ethacrynic acid (EA, pi) were used as inhibitors against CDNB-GSH conjugation. CHP inhibited the CDNB-GSH conjugation in mu-depressed livers more potently than in the non-depressed livers, probably because CHP is a specific inhibitor for alpha-class GST. Inhibition by CHP may therefore be used to detect livers which are low in mu-form. The inhibition by tPBO was found to be weak and the variability was small (CV of 9% in 17 livers). EA potently inhibited GST activity with its inhibition constant (Ki) 2,000-fold lower than that of CHP. The small individual variation in inhibition by EA (CV of 6%) supported that EA is a universal but potent inhibitor against major GSTs contained in human liver.
journal_name
Toxicologyjournal_title
Toxicologyauthors
Takamatsu Y,Inaba Tdoi
10.1016/0300-483x(94)90120-1subject
Has Abstractpub_date
1994-03-11 00:00:00pages
191-200issue
1-3eissn
0300-483Xissn
1879-3185pii
0300-483X(94)90120-1journal_volume
88pub_type
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