Glutathione resistance mechanism

Either the catalytic subunit or both subunits are overexpressed in several drug-resistant human cancer cells such as cisplatin-resistant ovarian cancer cells and melphalan-resistant prostate cancer cells, suggesting that elevated production of glutathione may induce drug-resistance mechanisms in these cancer cells (Figure... 

Another common resistance mechanism is enhanced detoxication in plants. Atrazine has an electrophilic carbon that may be attacked by glutathione, and biotypes of various weeds may have glutathione transferases that have a better ability to catalyze this reaction ... 

The data in Table 9.4 are extracted from data of Plaisance and Gronwald (1999) and show the difference in the activity of glutathione transferase. In this case there was no difference in the total amount of enzyme protein or activity toward the standard substrate. The inheritance of this resistance mechanism is in a nuclear gene. 

Dogs, rats, and rabbits metabolize fluoroacetate compounds to nontoxic metabolites, and excrete fluoroacetate and fluorocitrate compounds peak rate of excretion occurs during the first day after dosing and drops shortly thereafter. Rats dosed with radiolabeled 1080 at 5.0 mg/kg BW had 7 different radioactive compounds in their urine. Monofluoroacetate comprised oifly 13% of the urinary radioactive material, fluorocitrate oifly 11%, and an unidentified toxic metabolite 3% 2 nontoxic metabolites accounted for almost 73% of the urinary radioactivity. Animal muscle usually contained nondetectable residues of any 1080 component within 1-5 days of treatment. Defluorination occurred in the liver by way of an enzymic glutathione-dependent mechanism which in the brush-tailed opossum resulted in the formation of 5 -carboxymethylcysteine and free fluoride ion. A rapid rate of defluorination together with a low reliance on aerobic respiration favored detoxification of fluoroacetate rather than its conversion into fluorocitrate, and may account for the resistance of reptiles to 1080 when compared to mammals. 

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,... 

Yu SJ (1989) Purification and characterization of gluathione S-transferase from five phytophagous Lepidoptera. Pestic Biochem Physiol 35 97-105 Yu SJ (1992) Plant allelochemical-adapted glutathione transferases in Lepidoptera. In Mullin CA, Scott JG (eds) Molecular mechanisms of resistance to herbivorous pests to natural, synthetic and bioengineering control agents. Plenum, New York, pp 174-190 Yu SJ (1996) Insect glutathione S-transferases. Zool Stud 35 9-19... 

Studies on the mechanism of thiourea toxicity have shown that thioureas have a high degree of specificity for pulmonary endothelial cells and that thioureas require metabolic activation before toxic effects are manifested. Reduced glutathione levels have been associated with increased toxicity, but there is no evidence to suggest that the appearance of edema coincides with a decrease in glutathione. Furthermore, the induction of tolerance or resistance is not correlated with an increase in glutathione levels in rats. ... 

Possible biochemical mechanisms of resistance to alkylating agents include changes in ceU DNA repair capability, increases in cell thiol content (which in turn can serve as alternative and benign targets of alkylation), decreases in ceU permeability, and increased activity of glutathione transferases. Increased metaUothionein content has been associated with tumor cell resistance to cisplatin. 

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