Detoxification of 1-Chloro-2,4-dinitrobenzene in MCF7 Breast Cancer Cells Expressing Glutathione S-Transferase P1-1 and/or Multidrug Resistance Protein 1

Diah, Sri K.; Smitherman, Pamela K.; Townsend, Alan J.; Morrow, Charles S.

doi:10.1006/taap.1999.8672

Cited by 37 publications

(25 citation statements)

References 27 publications

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“…Indeed, we have shown that coexpression with GST of the glutathione conjugate efflux transporters, MRP1 or MRP2, is necessary to potentiate GSTmediated protection from the toxicities of the cancer drug chlorambucil (CHB) or the carcinogen 4-nitroquinoline 1-oxide (5-7). In these and other studies, high intracellular accumulation of the toxin-glutathione conjugate formed in the absence of MRP1 (or MRP2) is associated with increased toxicity whereas low intracellular toxin-conjugate accumulation resulting from MRP-dependent conjugate efflux is associated with cellular resistance (5,7,8). These results indicate that glutathione conjugates, especially when they accumulate to high intracellular levels, may themselves be directly or indirectly toxic.…”

mentioning

confidence: 58%

“…These results suggest that the glutathione conjugates, which accumulate within the cell in the absence of MRP, have some residual or novel toxicities. Indeed, in the absence of MRP1, GST-expressing MCF7 cell derivatives treated with only micromolar concentrations of CDNB or 4-nitroquinoline 1-oxide can rapidly accumulate millimolar concentrations of the respective glutathione conjugates, S-(2, 4-dinitrophenyl)-glutathione or 4-(glutathione-S-yl)-quinoline 1-oxide (5,7,8). Under similar conditions, MRP1-expressing cells are able to maintain very low intracellular levels of these conjugates.…”

Section: Role Of Mrp1 and Gst In Alkylating Agent Resistancementioning

confidence: 99%

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Role of Multidrug Resistance Protein 1 (MRP1) and Glutathione S-Transferase A1-1 in Alkylating Agent Resistance

Paumi

Ledford

Smitherman

et al. 2001

Journal of Biological Chemistry

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We investigated the role of phase II (conjugation) and phase III (efflux) detoxification of the anticancer drugs melphalan (MLP) and chlorambucil (CHB). Although both drugs are substrates of Alpha-class glutathione Stransferases (GST) and the monoglutathionyl conjugates formed in these enzymatic reactions are transported by MRP1, we found that GSTA1-1 and MRP1 acted in synergy to confer resistance to CHB but not to MLP (Morrow, C. S., Smitherman, P. K., Diah, S. K., Schneider, E., and Townsend, A. J. (1998) J. Biol. Chem. 273, 20114 -20120). To explain this selectivity of MRP1/GST-mediated resistance, we report results of side-byside experiments comparing the kinetics of MLP-versus CHB-glutathione conjugate: formation, product inhibition of GSTA1-1 catalysis, and transport by MRP1. The monoglutathionyl conjugate of CHB, CHB-SG, is a very strong competitive inhibitor of GSTA1-1 (K i 0.14 M) that is >30-fold more potent than that of the corresponding conjugate of MLP, MLP-SG (K i 4.7 M). The efficiency of GSTA1-1-mediated monoglutathionyl conjugate formation is more than 4-fold higher for CHB than MLP. Lastly, both CHB-SG and MLP-SG are efficiently transported by MRP1 with similar V max although the K m for CHB-SG (0.37 M) is significantly lower than for MLP-SG (1.1 M). These results indicate that MRP1 is required for GSTA1-1-mediated resistance to CHB in order to relieve potent product inhibition of the enzyme by intracellular CHB-SG formed. The kinetic properties of MRP1 are well suited to eliminate CHB-SG at pharmacologically relevant concentrations. For MLP detoxification, where product inhibition of GSTA1-1 is less important, GSTA1-1 does not confer resistance because of the relatively poorer catalytic efficiency of MLP-SG formation. Similar analyses can be useful for predicting the pharmacological and toxicological consequences of MRP and GST expression on cellular sensitivity to various other electrophilic xenobiotics.

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mentioning

confidence: 58%

Section: Role Of Mrp1 and Gst In Alkylating Agent Resistancementioning

confidence: 99%

Role of Multidrug Resistance Protein 1 (MRP1) and Glutathione S-Transferase A1-1 in Alkylating Agent Resistance

Paumi

Ledford

Smitherman

et al. 2001

Journal of Biological Chemistry

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“…In fact, this substance yielded significant information on detoxication by GSTs in general. Cells transfected with high amounts of very active cytosolic GST were actually more vulnerable to CDNB than control cells (Diah et al, 1999). Only when efficient glutathione conjugate export pumps were also present in the cells did increased glutathione conjugation afford protection.…”

Section: Toxicity and Localization Of The Glutathione Conjugatementioning

confidence: 93%

Reactive Intermediates and The Dynamics of Glutathione Transferases

Rinaldi

Eliasson²,

Swedmark³

et al. 2002

Drug Metab Dispos

123

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ABSTRACT:Reactive intermediates are a continuous burden in biology and several defense mechanisms have evolved. Here we focus on the functions of glutathione transferases (GSTs) with the aim to discuss the quantitative aspects of defense against reactive intermediates. Humans excrete approximately 0.1 mmol of thioether conjugates per day. As the amount of GST active sites in liver is Ϸ0.5 mmol, it appears that glutathione transferase catalysts are present in tremendous excess. In fact, the known catalytic properties of GSTs reveal that the enzymes can empty the liver glutathione (GSH) pool in a matter of seconds when provided with a suitable substrate. However, based on the urinary output of conjugates (or derivatives thereof), individual GSTs turn over (i.e., catalyze a single reaction) only once every few days. Glutathione transferase overcapacity reflects the fact that there is a linear relation between GST enzyme amount and protection level (provided that GSH is not depleted). Put in a different perspective, a few reactive molecules will always escape conjugation and reach cellular targets. It is therefore not surprising that signaling systems sensing reactive intermediates have evolved resulting in the increase of GSH and GST levels. Precisely for this reason, more moderately reactive electrophiles (Michael acceptors) are receiving growing interest due to their anticarcinogenic properties. Another putative regulatory mechanism involves direct activation of microsomal GST1 by thiol-reactive electrophiles through cysteine 49. The toxicological significance of low levels of reactive intermediates are of interest also in drug development, and here we discuss the use of microsomal GST1 activation as a surrogate detection marker.

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“…Nrf2 contributes to the induction of alpha-class GST isozymes in liver of acute cadmium or manganese intoxicated rats 19 . It was shown that in MCF7 breast cancer cells GST-π conjugation activity and multidrug resistance protein 1 (MRP1)-mediated conjugate efflux operate together to confer resistance to 1-chloro-2,4-dinitrobenzene (CDNB) cytotoxicity 20 . Interaction of antidepressants with GST-π and GST-α may reduce their availability and therapeutic activity.…”

Section: Introductionmentioning

confidence: 99%

Amitriptyline may have a supportive role in cancer treatment by inhibiting glutathione S-transferase pi (GST-π) and alpha (GST-α)

Kulaksiz-Erkmen

Dalmızrak

Dincsoy-Tuna

et al. 2011

Journal of Enzyme Inhibition and Medicinal Chemistry

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Detoxification of 1-Chloro-2,4-dinitrobenzene in MCF7 Breast Cancer Cells Expressing Glutathione S-Transferase P1-1 and/or Multidrug Resistance Protein 1

Cited by 37 publications

References 27 publications

Role of Multidrug Resistance Protein 1 (MRP1) and Glutathione S-Transferase A1-1 in Alkylating Agent Resistance

Role of Multidrug Resistance Protein 1 (MRP1) and Glutathione S-Transferase A1-1 in Alkylating Agent Resistance

Reactive Intermediates and The Dynamics of Glutathione Transferases

Amitriptyline may have a supportive role in cancer treatment by inhibiting glutathione S-transferase pi (GST-π) and alpha (GST-α)

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