Cysteine, sulfite, and glutamate toxicity: a cause of ALS?

BACKGROUND: Amyotrophic lateral sclerosis (ALS) of nonmutant superoxide dismutase (SOD) type may be caused by toxicity of the reduced glutathione (GSH) precursors glutamate and cysteine, and sulfite (a metabolite of cysteine), which accumulate when one or more of the enzymes needed for GSH synthesis are defective. OBJECTIVES: A case is examined where the patient exhibited elevated sulfur on a hair mineral analysis, elevated blood cysteine, positive urine sulfite, elevated urine glutamate, and low whole blood GSH. During the time when strict dietary and supplement measures normalized the patient's whole blood GSH, blood cysteine, and urine sulfite, the patient did not experience additional physical decline. The possible causes of abnormalities of the patient's laboratory test results, as well as the nutrition measures used to normalize them, are discussed in relationship to the functions and importance of cysteine, sulfite, and glutamate in glutathione metabolism in ALS. CONCLUSIONS: Since elevated plasma cysteine has been reported in other ALS patients, sulfite and cysteine toxicity may be involved in other cases of ALS. Patients with ALS with nonmutant-SOD should be tested for sulfite toxicity, cysteine, glutamate and GSH levels, and whether they have low levels of GSH metabolism enzymes. Since glutamate metabolism appears to be inhibited by sulfite, research on the effect of sulfite on glutamate levels in patients with ALS should be pursued. Life might be prolonged in those patients with ALS with sulfite toxicity by closely monitoring the blood cysteine and urine sulfite levels and minimizing their dietary intake, as well as increasing GSH by using sublingual GSH. A long-term solution might be found through research to determine methods to increase GSH synthesis without using sulfur-containing supplements that may add to the cysteine and sulfite toxicity.

Effects of endocrine disruptors on dehydroepiandrosterone sulfotransferase and enzymes involved in PAPS synthesis: genomic and nongenomic pathways.

BACKGROUND: Sulfation plays an important role both in detoxification and in the control of steroid activity. Studies in rodents have shown that the conversion of dehydroepiandrosterone (DHEA) to DHEA-sulfate is involved in learning and the memory process. METHODS: The effects of a range of plasticizers and related compounds commonly encountered in the environment were evaluated kinetically against human DHEA sulfotransferase (SULT 2A1) and by reverse transcriptase-polymerase chain reaction (RT-PCR) against several enzymes involved in the synthesis of the sulfotransferase cofactor adenosine 3'-phosphate 5'-phosphosulfate (PAPS). RESULTS: We found that several of the chemicals acted as competitive inhibitors of SULT 2A1 (K(i) for 4-tert-octylphenol is 2.8 microM). Additionally, after treatment of TE 671 cells with 0.005-0.5 microM 4-n-octylphenol, bis(2-ethylhexyl)phthalate, and diisodecyl phthalate, real-time RT-PCR showed dose-dependent decreases in the steady-state mRNA levels of cysteine dioxygenase type I, sulfite oxidase, and 3'-phosphate 5'-phosphosulfate synthase I. CONCLUSIONS: These data suggest that environmental contaminants may exert effects on neuronal function both by direct inhibition of sulfotransferase enzymes and by interrupting the supply of PAPS, which has wider implications for endocrine disruption and xenobiotic metabolism.

The effect of plasticisers on "sulphate supply" enzymes.

Sulphation is important in xenobiotic detoxification and in steroid and thyroid hormones synthesis, transport and metabolism. Potential endocrine disrupting actions of plasticisers were assessed by studying effects on cell viability, cell proliferation and expression of enzymes (cysteine dioxygenase, sulphite oxidase, PAPS synthase I and II) involved in the synthesis of the cofactor, PAPS, for steroid sulphotransferases. TE 671 cells were used to study the effects of exposure to alkylphenols and alkylphenolethoxylates, bisphenol A, bisphenol A methacrylate, alkyladipates, dialkyl phthalates and resorcinol. The lactate dehydrogenase assay and CellTiter 96) AQ(ueous) One Solution Cell Proliferation Assay were used to measure cytotoxicity and cell proliferation, respectively. Steady-state mRNA was assessed by semi-quantitative RT-PCR and real time RT-PCR. None of the compounds tested was cytotoxic in TE 671 cells, however, cell proliferation was significantly increased with 0.005-0.5 microM dioctyl phthalate, diisodecyl phthalate (DIP) and butylbenzyl phthalate (P<0.05, n = 4). Real time RT-PCR showed dose-dependent decreases in steady-state mRNA levels of all the enzymes studied (P<0.05, n = 4) with 0.005-0.5 microM octylphenol, bis (2-ethylhexyl) phthalate and DIP treatment. Endocrine disrupting effects of some plasticisers may be a consequence of modulation of expression of enzymes supplying PAPS for hormone sulphation.