Acivicin-induced alterations in renal and hepatic glutathione concentrations and in γ-glutamyltransferase activities
详细信息 查看全文
- 作者：Lantum ; Hoffman B.M. ; Iyer ; Ramaswamy A. ; Anders ; M.W.
- 关键词：γ ; -GT ; γ ; -glutamyltransferase ; Compound A ; 2-(fluoromethoxy)-1 ; 1 ; 3 ; 3 ; 3-pentafluoro-1-propene ; Glutathione ; γ ; -Glutamyltransferase ; Acivicin ; Haloalkenes ; Glutathione S-conjugates ; Mercapturic acid pathway ; β ; -Lyase ; 2-(Fluoromethoxy)-1 ; 1 ; 3
- 刊名：Biochemical Pharmacology
- 出版年：2004
- 出版时间：April 1, 2004
- 年：2004
- 卷：67
- 期：7
- 页码：1421-1426
- 全文大小：133 K
文摘
γ-Glutamyltransferase (γ-GT) catalyzes the hydrolysis of glutathione, glutathione S-conjugates, and γ-substituted l-glutamate derivatives. Acivicin is an irreversible inhibitor of γ-GT that has been used to study the role of γ-GT in glutathione homeostasis and glutathione-dependent bioactivation reactions. The present studies were undertaken because of reported conflicting effects of acivicin on the nephrotoxicity of some haloalkenes that undergo glutathione-dependent bioactivation. The objective of this study was to test the hypothesis that acivicin may alter renal glutathione concentrations; acivicin-induced changes in renal glutathione concentrations may alter the susceptibility of the kidney to the nephrotoxic effects of haloalkenes. Hence, diurnal and acivicin-induced changes in renal and hepatic glutathione concentrations along with renal and hepatic γ-GT activities were investigated. The previously observed diurnal variations in hepatic glutathione concentrations in fed rats were confirmed, but no diurnal variations were observed in renal glutathione concentrations or in renal or hepatic γ-GT activities. Renal and hepatic glutathione concentrations and γ-GT activities were measured in tissue homogenates from rats given 0, 0.1, or 0.2mmol acivicin/kg (i.p.) and killed 0, 2, 4, 8, 12, or 24hr later. Renal glutathione concentrations were increased above control values in acivicin-treated rats, whereas acivicin had no effect on hepatic glutathione concentrations. Renal γ-GT activities decreased within 2hr after giving acivicin and remained decreased for 24hr. Acivicin had no effect on hepatic γ-GT activities, except at 24hr after treatment when values in acivicin-treated rats were elevated compared with controls. Although the present studies do not afford an explanation of the mechanism whereby acivicin increases the nephrotoxicity of some haloalkenes, they do indicate that acivicin is not a reliable probe to investigate the role of γ-GT in haloalkene-induced nephrotoxicity.