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PubMed1995

Effect of ifosfamide treatment on glutathione and glutathione conjugation activity in patients with advanced cancers.

Several studies have suggested that the glutathione/glutathione S-transferase (GSH/GST) system is involved in resistance of tumors toward ifosfamide and other cytostatic agents. Besides, ifosfamide metabolites (in vitro) as well as ifosfamide treatment (in vivo) have been shown to decrease cellular GSH availability. In the present study, the in vivo effects of three different ifosfamide treatment schedules on the GSH/GST system were studied in patients with advanced cancers (n = 24): continuous i.v. infusions of 1300 mg/m2 daily for 10 days and 5000 mg/m2/day for 24 h, as well as a 4-h infusion of 3000 mg/m2 daily for 3 days. The GSH/GST system was characterized by administering bromisoval, a probe drug to assess GSH conjugation activity in vivo, as well as by daily monitoring of GSH concentrations in blood cells and plasma. Bromisoval pharmacokinetics was assessed before and at the end of the ifosfamide treatment. Blood cell GSH levels decreased significantly (P < 0.05) during the 3- and 10-day ifosfamide treatment schedules; the 24-h treatment had no effect. The ifosfamide treatment schedules had only minimal effects on bromisoval pharmacokinetics. Assuming that the kinetics of the probe drug provide an accurate reflection of enzyme activity, this suggests that GST activity remains unchanged. Because GSH conjugation of bromisoval enantiomers requires both GST activity and GSH availability, these results also indicate that, despite the 35% decrease in GSH in blood cells of two patient groups, the GSH availability of the cancer patients was not rate-limiting for GSH conjugation of bromisoval enantiomers. If GSH levels in blood cells reflect those in tumors/other tissues, the present results indicate that ifosfamide may be used clinically to decrease GSH levels. However, whether a 35% decrease is sufficient to increase tumor sensitivity toward (other) cytostatics remains uncertain.

Adult↗
PubMed1986

The role of glutathione in the toxicity of xenobiotic compounds: metabolic activation of 1,2-dibromoethane by glutathione.

Unstable metabolites may arise during the metabolism of xenobiotic compounds with enzyme systems other than the cytochrome P-450 system. This depends on the enzyme system involved and the structure of the xenobiotic compound being metabolized. Normally detoxifying pathways may transform selected chemicals into toxic metabolites. In our laboratory we have demonstrated that DBE is metabolized by both cytochrome P-450 and GSH S-transferases. Although the cytochrome P-450 metabolite is reactive and will covalently bind to protein and nucleic acid to some extent, and the GSH S-transferase system conjugates it and under conditions of low DBE exposure is able to detoxify it. In contrast, GSH S-transferase catalyzes the direct conjugation of GSH with DBE. This can result in formation of a reactive intermediate that preferentially binds to nucleic acids and is responsible for the DNA damage observed following DBE exposure. The selective toxicity of this xenobiotic compound may be due to the preponderance of activating GSH conjugating enzymes in the extrahepatic organs. However, this difference alone does not appear sufficient to explain the selection of extrahepatic organs as sites of DBE-induced toxicity.

Animals↗