Glutathione inactivation

Thiols such as cysteine, N-acetyl-cysteine, mercatoproplonyl-glyclne, and reduced glutathione Inactivate the mutagenic properties of aflatoxin B- by forming adducts at the electrophilic... 

Plasmid- ortransposon-mediated resistance occurs by inactivation ofthe antibiotic. Fosfomycin is combined with glutathione intracellularly to produce a compound lacking in antibacterial activity. The gene encoding the enzyme catalysing this reaction has been designated/or-r. 

Blum, J. and Friedovich, I. (1985). Inactivation of glutathione peroxidase by superoxide radical. Arch. Biochem. Biophys. 240, 500-508. 

The common mechanisms of drug resistance in ovarian cancer include (1) alteration of drug inactivation by agents such as glutathione-S-transferase (GST), (2) enhanced DNA repair,... 

On the other hand, microsomes may also directly oxidize or reduce various substrates. As already mentioned, microsomal oxidation of carbon tetrachloride results in the formation of trichloromethyl free radical and the initiation of lipid peroxidation. The effect of carbon tetrachloride on microsomes has been widely studied in connection with its cytotoxic activity in humans and animals. It has been shown that CCI4 is reduced by cytochrome P-450. For example, by the use of spin-trapping technique, Albani et al. [38] demonstrated the formation of the CCI3 radical in rat liver microsomal fractions and in vivo in rats. McCay et al. [39] found that carbon tetrachloride metabolism to CC13 by rat liver accompanied by the formation of lipid dienyl and lipid peroxydienyl radicals. The incubation of carbon tetrachloride with liver cells resulted in the formation of the C02 free radical (identified as the PBN-CO2 radical spin adduct) in addition to trichoromethyl radical [40]. It was found that glutathione rather than dioxygen is needed for the formation of this additional free radical. The formation of trichloromethyl radical caused the inactivation of hepatic microsomal calcium pump [41]. 

Catalase and glutathione peroxidase provide two important cellular systems for eliminating H202. Catalase, a 56kDa cytosolic hemoprotein homotetramer that can act without a cofactor, although it may bind NAD(P)H, functions as a peroxidase to convert H202 to water. It can be irreversibly inactivated by oxidation and demonstrates decreased activity after ischemia-reperfusion. Catalase is more abundant in astrocytes than in neurons and in white matter than in gray matter, but it can be induced in neurons by neurotrophins. There is substantially less catalase activity in brain than in other tissues, such as liver. 

Intracellular thiolate ligands such as glutathione (GSH, the tripeptide y-L-Glu-L-Cys-Gly) are believed to inactivate cisplatin because the reactions with cisplatin tend to be irreversible (35). Elevated levels of GSH have been observed in cisplatin-resistant cells. Recently, it has been shown that an MRP gene, which encodes a human ATP-dependent glutathione S-conjugate export pump (GS-X pump), is expressed at higher levels in cisplatin-resistant (HL-60/R-CP) cells than in sensitive cells (36). The GS-X pump may contribute to the excretion of Pt-GS complexes from cells (37). 

However, the temptation to link glutathione (GSH) adducts to MBI must be avoided since the identification of metabolite adducts with GSH does not confirm MBI, albeit it may be an indicator of other adverse drug reactions (Walgren et al., 2005). By definition, exogenous nucleophiles such as GSH should offer no protection from MBI [161], and in principle, even when GSH adducts are formed from the same chemical entity responsible for MBI, the exogenous adducts themselves may not be related to the enzyme-inactivating species [174]. 

Together with glutathione conjugation, hydration is a major pathway in the inactivation and detoxification of arene oxides. Exceptions to this rule will be treated when discussing polycyclic aromatic hydrocarbons. Arene oxides are good substrates for microsomal EH, as evidenced in Table 10.1, where hydration of selected arene oxides, alkene oxides, and cy-cloalkene oxides by purified rat liver epoxide hydrolase is compared. The hy- ... 

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