Human CD34+ cells do not express glutathione S-transferases alpha

Czerwiński, Maciej; Kiem, HP; Jt, Slattery

doi:10.1038/sj.gt.3300381

Cited by 25 publications

(27 citation statements)

References 2 publications

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“…The reasons for this remain unclear, although low DNA repair activity and lack of GST ␣ expression in bone marrow CD34 ϩ cells have been implicated (55,56). Toxicity manifests clinically as pancytopenia, and it is dose-limiting for several chemotherapeutic alkylating agents.…”

Section: Discussionmentioning

confidence: 99%

Polymorphism in glutathione S -transferase P1 is associated with susceptibility to chemotherapy-induced leukemia

Allan

Wild

Rollinson

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

236

139

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Glutathione S -transferases (GSTs) detoxify potentially mutagenic and toxic DNA-reactive electrophiles, including metabolites of several chemotherapeutic agents, some of which are suspected human carcinogens. Functional polymorphisms exist in at least three genes that encode GSTs, including GSTM1, GSTT1, and GSTP1. We hypothesize, therefore, that polymorphisms in genes that encode GSTs alter susceptibility to chemotherapy-induced carcinogenesis, specifically to therapy-related acute myeloid leukemia (t-AML), a devastating complication of long-term cancer survival. Elucidation of genetic determinants may help to identify individuals at increased risk of developing t-AML. To this end, we have examined 89 cases of t-AML, 420 cases of de novo AML, and 1,022 controls for polymorphisms in GSTM1, GSTT1, and GSTP1 . Gene deletion of GSTM1 or GSTT1 was not specifically associated with susceptibility to t-AML. Individuals with at least one GSTP1 codon 105 Val allele were significantly over-represented in t-AML cases compared with de novo AML cases [odds ratio (OR), 1.81; 95% confidence interval (CI), 1.11–2.94]. Moreover, relative to de novo AML, the GSTP1 codon 105 Val allele occurred more often among t-AML patients with prior exposure to chemotherapy (OR, 2.66; 95% CI, 1.39–5.09), particularly among those with prior exposure to known GSTP1 substrates (OR, 4.34; 95% CI, 1.43–13.20), and not among those t-AML patients with prior exposure to radiotherapy alone (OR,1.01; 95% CI, 0.50–2.07). These data suggest that inheritance of at least one Val allele at GSTP1 codon 105 confers a significantly increased risk of developing t-AML after cytotoxic chemotherapy, but not after radiotherapy.

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Section: Discussionmentioning

confidence: 99%

Polymorphism in glutathione S -transferase P1 is associated with susceptibility to chemotherapy-induced leukemia

Allan

Wild

Rollinson

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

236

139

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“…It is of interest that hGSTA1 is not expressed in fetal liver HSC, as this alpha class GST has comparatively high constitutive expression in most human tissues (Gallagher and Gard- . It has been reported that hGSTA1 mRNA is not expressed in CD34 ϩ cells derived from human bone marrow (Czerwinski et al, 1997). Because the hGSTA1-1, hGSTA2-2, and hGSTA4-4 proteins are the dominant GST isoforms that protect against oxidative damage (Hayes and Pulford, 1995;Hubatsch et al, 1998), lack of these isoforms in HSC suggests that GST may not constitute an important pathway of protection against byproducts of oxidative stress in these cells.…”

Section: Discussionmentioning

confidence: 99%

“…There are very few reports in the literature of biotransformation enzyme expression in HSC, with a few studies centering on gene expression and catalytic activities using CD34 ϩ cells from bone marrow or peripheral blood (Czerwinski et al, 1997;Bernauer et al, 2000;Kousalova et al, 2004;Czekaj et al, 2005). For example, CYP2E1 is present in CD34 ϩ stem cells derived from human, rat, and rabbit bone marrow, and human CD34 ϩ cells from blood have functional CYP2E1 activity toward chlorzoxazone (Kousalova et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Cytochrome P450 and GlutathioneS-Transferase mRNA Expression in Human Fetal Liver Hematopoietic Stem Cells

et al. 2006

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ABSTRACT:During fetal development, the liver serves as the primary hematopoietic organ in which hematopoietic stem cells (HSC) capable of initiating long-term hematopoiesis comprise a large proportion of the hepatic cell population. Although HSC are potential targets for transplacental chemicals, little is known regarding their xenobiotic biotransformation ability. We quantitated the steady-state mRNA expression of six cytochrome P450 (P450) and 11 glutathione Stransferase (GST) isoforms in CD34؉ -selected HSC isolated from second trimester human fetal liver donors, genotyped donors for polymorphic hGSTM1 and hGSTT1 status, and analyzed gene expression in HSC relative to total liver from donors of similar gestational ages. Several P450 isoforms, including CYP1A1, CYP2E1, CYP3A4, and CYP3A5, were expressed at low levels in HSC (relative mRNA expression CYP3A5 > CYP1A1 > CYP2E1 > CYP3A4).CYP1A2 and CYP3A7 were not detected in HSC. The CYP3A4/5 mRNA expression in HSC was accompanied by detectable CYP3A protein and low midazolam oxidation activity. Several GST isoforms, including hGSTM1, hGSTM2, hGSTM4, and hGSTP1, were significantly higher in HSC as compared with total fetal liver. With the exception of hGSTA4, alpha class GST were not detected in HSC. GST expression in HSC was accompanied by substantial GST catalytic activity toward 1-chloro-2,4-dinitrobenzene. In summary, our data indicate that fetal liver CD34 ؉ -derived HSC constitutively express several P450 isoforms at low levels relative to total hepatic cell populations but have a higher capacity for GST conjugation reactions through mu and pi class isoforms. The functional ramifications of these observations are discussed relative to the sensitivity of human fetal HSC to transplacental chemical injury.

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“…Hematopoietic stem cells do not express GSTA1, which might explain the sensitivity of these cells to busulphan. 35 However, hematopoietic cells express other GST isoforms whose activity has to be considered when cellular content of GSH is increased by N-acetylcysteine. 36 In the present study we investigated the pharmacodynamic relationship between AUC and busulphan cytotoxicity in human CD34 + cells in vitro.…”

mentioning

confidence: 99%

The effect of modulation of glutathione cellular content on busulphan-induced cytotoxicity on hematopoietic cells in vitro and in vivo

Hassan

Hellström‐Lindberg

Alsadi

et al. 2002

Bone Marrow Transplant

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Summary:Busulphan is used in conditioning regimens prior to SCT. A relationship between exposure to busulphan, expressed as an area under the plasma concentration time curve (AUC), and effect and/or adverse effects, such as veno-occlusive disease (VOD), was reported. Exhaustion of glutathione (GSH) contributes to VOD and modulation of intracellular levels of GSH influences bulsulphan-induced toxicity in hepatocytes. Thus, increase of GSH might serve as prophylaxis against VOD. However, it should not interfere with the myeloablative effects of busulphan. We investigated the relationship between exposure to busulphan, and its in vitro toxicity to CD34 + hematopoietic progenitors from volunteers using clonogenic assays. Busulphan inhibited colony formation by CD34 + cells in an AUC-dependent manner. Myeloid progenitors were more sensitive than erythroid progenitors, expressed as 100% inhibition of colony formation (68.7 ؎ 7.5 g.h/ml and 140.3 ؎ 35.7, respectively). The observed exposure corresponds to the total AUC obtained in patients treated with busulphan (1 mg/kg/day) for 4 days. Secondly, we studied the effect of modulation of GSH cellular levels on busulphaninduced toxicity in vitro in CD34 + cells from volunteers, and in vivo in bone marrow cells from Balb/c mice. The intracellular concentration of GSH was increased or decreased by treatment with N-acetylcysteine or buthionine sulfoximine, respectively. Neither in vitro nor in vivo treatment with GSH modulators affected the hematological toxicity of busulphan. Thus, N-acetylcysteine would not interfere with the myeloablative effect of busulphan and therefore it is a potential candidate for VOD prophylaxis during busulphan-based conditioning regimens.

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Human CD34+ cells do not express glutathione S-transferases alpha

Cited by 25 publications

References 2 publications

Polymorphism in glutathione S -transferase P1 is associated with susceptibility to chemotherapy-induced leukemia

Polymorphism in glutathione S -transferase P1 is associated with susceptibility to chemotherapy-induced leukemia

Cytochrome P450 and GlutathioneS-Transferase mRNA Expression in Human Fetal Liver Hematopoietic Stem Cells

The effect of modulation of glutathione cellular content on busulphan-induced cytotoxicity on hematopoietic cells in vitro and in vivo

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