Role of glutathione in the biliary excretion of the arsenical drugs trimelarsan and melarsoprol

Gregus, Zoltán; Gyurasics, Ágnes

doi:10.1016/s0006-2952(00)00263-x

Cited by 31 publications

(16 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It is well known that the transport of arsenic from the liver to bile is dependent on GSH in rat model [44]. The study supported in vivo evidence where the conjugation of arsenic with GSH is important for its biliary excretion via the MRP2 transporter [45,46]. Furthermore, a previous report demonstrated that a dose of 15 mg arsenite/kg caused 50% lethality in MRP1-null mice but only 17% of that in the wild-type mice [47].…”

Section: Efflux Of Arsenicsupporting

confidence: 75%

Application of Arsenic Trioxide Therapy for Patients with Leukaemia

Yuan

Yoshino

Kaise

et al. 2010

Biological Chemistry of Arsenic, Antimony and Bismuth

View full text Add to dashboard Cite

Section: Efflux Of Arsenicsupporting

confidence: 75%

Application of Arsenic Trioxide Therapy for Patients with Leukaemia

Yuan

Yoshino

Kaise

et al. 2010

Biological Chemistry of Arsenic, Antimony and Bismuth

View full text Add to dashboard Cite

“…Recent evidence showed that AA enhanced the sensitivity of myeloid and lymphoid malignant cells to As 2 O 3 in vitro through the oxidative pathway [6][7][8] and the increased level of ROS was the result of GSH depletion. GSH was a main nonprotein antioxidant in the cell, and it could clear away the superoxide anion free radical and provide electrons for enzymes such as GPx, which reduce H 2 O 2 to H 2 O. Additionally, GSH could combine with As 2 O 3 directly, forming a transient As(GS) 3 molecule, which was more easily excreted through drug efflux pumps [18][19][20][21] . In the present study, ROS was found to be a critical contributor to the potentiating effect of AA on As 2 O 3 -induced apoptosis in HepG2 cells.…”

Section: Discussionmentioning

confidence: 99%

Role of oxidative stress in the apoptosis of hepatocellular carcinoma induced by combination of arsenic trioxide and ascorbic acid1

Tang

et al. 2006

Acta Pharmacologica Sinica

137

View full text Add to dashboard Cite

Aim: The present study was designed to determine the possible pathway underlying the enhancement of apoptosis induced by the combined use of arsenic trioxide (As2O3) and ascorbic acid (AA). Methods: The level of intracellular reactive oxygen species (ROS) was detected by means of flow cytometry analysis with an oxidation‐sensitive fluorescent probe (6‐carboxy‐2′,7′dichlorodihydrofluorescein diacetate) uploading. The activity of glutathione (GSH), glutathione peroxidase (GPx), and superoxide dismutase (SOD) were detected by biochemical methods. The mitochondrial membrane potential was measured by flow cytometry analysis with rhodamine 123 staining. Bcl‐2, Bax, and p 17 subunit of caspase‐3 were analyzed using the Western blot method. The apoptosis rate was determined by flow cytometry with annexin‐V/propidium iodide staining. Results: Compared with As2O3 (2.0 μmol/L) treated alone, As2O3 (2.0 μmol/L) in combination with AA (100 μmol/L) decreased intracellular GSH content from 101.30±5.76 to 81.91±3.12 mg/g protein, and increased ROS level from 127.61±5.12 to 152.60±5.88, which was represented by the 2, 7‐dichlorofluorescein intensity. The loss of mitochondria membrane potential was increased from 1269.97±36.11 to 1540.52±52.63, which was presented by fluorescence intensity. The p17 subunit of caspase‐3 expression was increased approximately 2‐fold. However, SOD and GPx depletion and the ratio of Bcl‐2 to Bax were equal to that of As2O3 treated alone (P>0.05). When the ROS scavenger, N‐acetyl‐L‐cysteine, was added to As2O3 and AA combined treatment group, the apoptosis rate decreased from 15.60 %±1.14% to 9.48%±0.67%, and the ROS level decreased from 152.60±5.88 to 102.77±10.25. Conclusion: AA potentiated As2O3‐induced apoptosis through the oxidative pathway by increasing the ROS level. This may be the result of depleting intracellular GSH. It may influence the downstream cascade following ROS, including mitochondria depolarization and caspase‐3 activation. However, SOD and GPx depletion and the ratio of Bcl‐2 to Bax influenced by As2O3was not found to be potentiated by AA.

show abstract

“…1a, b); the authors had reported that these compounds are mainly excreted in the bile (Cristau et al 1975). This point was confirmed by Gregus and Gyurasics (2000) who have demonstrated that melarsoprol reacted with glutathione (GSH) and glucuronic acid. Nevertheless, arsthinol is less hydrophobic and is significantly excreted in urine (Cristau et al 1973) (5.07% of the dose for mice and 20.21% for guinea pigs) but the identity of its metabolites remains unexplored.…”

Section: Introductionmentioning

confidence: 63%

“…Thus, conjugation with GSH was found to be important in the elimination of dithiarsolanes; however, glucuronidation is also involved (Fig. 6d) (Gregus and Gyurasics 2000).…”

Section: In Vitro Experimentsmentioning

confidence: 97%

Speciation of arsenic in urine following intravenous administration of arsthinol in mice

Ajana¹,

Astier²,

Gibaud³

2010

Eur J Drug Metab Pharmacokinet

View full text Add to dashboard Cite

Recent investigations have shown that arsthinol, a trivalent organoarsenic compound (dithiarsolane), has been active in vitro on leukemia cell lines and offers a better therapeutic index than arsenic trioxide, as estimated by the ratio LD50/IC50. To complete our understanding of its urinary excretion, a sensitive method using liquid chromatography coupled with mass spectrometry (LC-MS) was used. Mice were injected intravenously with a single dose of arsthinol at 0.2 mmol/kg of body weight. The amount of total arsenic in tissues and body fluids was determined by a colorimetric method and urine metabolites were analyzed on a C18 Acclaim PepMap 100 A column by LC-MS. Our results showed that only three arsenic species (acetarsol, acetarsol oxide and arsthinol) were detected in the first 24-h urine. Overall, this study confirms that the hydrolysis of dithiarsolanes to arsenoxides (i.e. acetarsol oxide) can be followed by an oxidation in arsonic acids (i.e. acetarsol). All these compounds are excreted in the urine.

show abstract

Role of glutathione in the biliary excretion of the arsenical drugs trimelarsan and melarsoprol

Cited by 31 publications

References 25 publications

Application of Arsenic Trioxide Therapy for Patients with Leukaemia

Application of Arsenic Trioxide Therapy for Patients with Leukaemia

Role of oxidative stress in the apoptosis of hepatocellular carcinoma induced by combination of arsenic trioxide and ascorbic acid1

Speciation of arsenic in urine following intravenous administration of arsthinol in mice

Contact Info

Product

Resources

About