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Formation of glutathione (GSH) conjugates from 3‐(3,5‐dichlorophenyl)‐2,4‐thiazolidinedione (DCPT) by rat liver microsomes
Author(s) -
Crincoli Christine M.,
Patel Niti N.,
Harvison Peter J.
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.6.a813-a
Subject(s) - glutathione , troglitazone , chemistry , microsome , thiazolidinedione , metabolism , conjugate , biochemistry , pharmacology , endocrinology , enzyme , diabetes mellitus , peroxisome , biology , mathematical analysis , mathematics , type 2 diabetes , gene
DCPT is hepatotoxic in male Fischer 344 rats. The thiazolidinedione (TZD) ring of DCPT is also present in the insulin‐sensitizing agents used for treatment of type II diabetes. One member of this group, troglitazone (TGZ), was withdrawn from clinical use due to hepatotoxicity. Studies suggest that metabolism of the TZD ring may be involved in the liver damage associated with TGZ. Similarly, we believe metabolism plays a role in converting DCPT to a hepatotoxic species. In an effort to determine if reactive intermediates could be produced from DCPT, GSH trapping experiments were conducted. Incubations were carried out using rat liver microsomes in the presence of DCPT, GSH and an NADPH generating system. Samples were analyzed by HPLC with UV or mass spec detection. We found that DCPT underwent hydrolysis to [[(3,5‐dichlorophenyl)amino]carbonyl]thioglycolic acid (DCTA). Furthermore, we also obtained evidence for a GSH conjugate of 3,5‐dichlorophenyl isocyanate (DCPI) in the incubations. Formation of both products increased with time and appeared to be microsomal‐, but not NADPH‐dependent. We have previously shown that DCTA is not hepatotoxic in rats. In contrast, isocyanates are known to be chemically reactive and potentially toxic compounds. The mechanism of formation of DCPI formation and whether it contributes to DCPT hepatotoxicity requires further study. Supported by PHS grant ES012499.