Glutathione synthesis inhibition

Gotoh, N., Graham, A., Niki, E. anel Darley-Usmar, V.M. (1993). Inhibition of glutathione synthesis increases the toxicity of oxidised LDL to human monoctites and macrophages. Biochem. J. 296, 151-154. 

Dethmers, J.K. and Meister, A. (1981). Glutathione export by human lymphoid cells depletion of glutathione by inhibition of its synthesis decreases export and increases sensitivity to irradiation. Proc. Natl Acad. Sci. USA 78, 7492-7496. 

On the other hand, hydroquinone (3 pmol/L) prevented the staurosporine-induced apoptosis of HL-60 and the IL-3-dependent murine myeloblastic (32D) cell line it also prevented apoptosis of the 32D cells observed in the absence of IL-3. The myeloperoxidase inhibitor indomethacin opposed the effect of hydroquinone on staurosporine-induced apoptosis of HL-60 cells (Hazel et al., 1995, 1996b). Pretreatment of human leukaemia cells ML-1 with buthionine sulfoximine (100 pmol/L for 24 h), in order to decrease their glutathione content, increased the susceptibility of these cells to hydroquinone-induced inhibition of differentiation caused by phorbol acetate pretreatment with l,2-dithiole-3-thione, which induces reduced glutathione synthesis, prevented the differentiation inhibition of hydroquinone. Treatment of DBA/2 mice with 1,2-dithiole-3-thione, which increased the activity of quinone reductase of bone-marrow stromal cells by 50%, decreased the susceptibility of these cells towards hydroquinone (Trush et al., 1996). 

M. Runnegar, K. Shou-Ming, Z. Ya-Zhen and C. Shelly, Inhibition of reduced glutathione synthesis by cyanobacterial alkaloid cylindrospermopsin in cultured rat hepatocytes, Biochem. Pharmacol., 49 (1995) 219-255. 

Castagne V, Cuenod M, Do KQ. 2004a. An animal model with relevance to schizophrenia Sex-dependent cognitive deficits in osteogenic disorder-Shionogi rats induced by glutathione synthesis and dopamine uptake inhibition during development. Neuroscience 123 821-834. 

Runnegar, M.T.C, King, S.M., Zhong, Y.Z., and Lu, S.C. 1995. Inhibition of reduced glutathione synthesis by cyanobacterila alkaloid cylindrospermopsin in cultured rat hepatocytes. Biochemistry and Pharmacology 49(2) 219-225. 

Mayer RD, Lee KE, and Cockett AT. Inhibition of cisplatin-induced nephrotoxicity in rats by buthionine sulfoximine, a glutathione synthesis inhibitor. Cancer Chemotherapy and Pharmacology 20 207-210,1987. 

The hormonal regulation of GCS expression has special physiological relevance. Phenylephrine, glucagon or dibutyryl cAMP inhibit GCS activity, which decreases glutathione synthesis and leads to glutathione depletion in rat hepatocytes [26,27]. The loss of GCS activity induced by these stress hormones is mediated by phosphorylation of the catalytic GCS subunit due to activation of protein kinase A, protein kinase C or Ca -calmoduhn kinase [28]. Consequently, the stress response diminishes GSH synthesis, which may increase the availability of cysteine for the synthesis of stress proteins [14]. 

G12. Griffin, O. W., and Meister, A., Potent and specific inhibition of glutathione synthesis by buthionine sulphoxamine (S-n-Butyl homocysteine sulphoximine). J. Biol. Chem. 234, 7558-7560 (1979). 

When glutathione synthesis was inhibited by bu-thionine sulfoximine so that were was a 50 % depletion of glutathione, the immortalised rat mesencephalic cell line CSM14.1.4 showed an enhanced synergistic toxicity of sulphite and peroxynitrite (Marshall et al. 1999). Because sulphite is present normally in the brain as a product of cysteine metabolism, and because increased peroxynitrite formation has been reported in Parkinson s disease, these events might contribute to neuronal death. 

Fig. 17.5 Effect of nitric oxide on the synthesis of methionine and S-adenosylmethionine and methylation reactions. NO inhibits methyltetrahydrofolate reductase (MTR). This results in a decrease in tetrahydrofolate (FH4) and methionine. Additional reduction in the FH4 level may occur by the NO-induced oxidation of ferritin, a compound that inhibits the proteasomal degradation of FH4. NO affects SAM synthesis not only by inducing a decrease in methionine synthesis but also by directly inhibiting the liver-specific methyl-thioadenosyltransferase I/III (MATI/III) isozymes. The fall in SAM level cannot be fully compensated by an increase in the extrahepatic isozyme MATH, since this enzyme is inhibited by its reaction product. The reduction in homocysteine utilization for methionine synthesis may result in homocysteine accumulation. This probably does not lead to a consistent rise in cystathionine and reduced glutathione synthesis, dne to a reduced stabilization of cystathionine P-synthase (CBS) by SAM. Consequently, an inciea.se in SAH, associated with a decrease in the SAM/SAH ratio, inhibits methyltransferases (MT) and DNA methylation. The reduction in SAM level may decrease IicBa activation, thus favoring NF-kB activity...

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