Administration of sodium hydrosulfide (NaHS), an alkali salt of hydrogen sulfide (H2S) at doses of 10 and 30 mg/kg, corresponding to sublethal and lethal doses (0.66 and 2.0 X LD50) resulted in significant increases in regional catecholamine levels of the rat brain only after the dose of 2.0 x LD50 of NaHS. Whereas the cortex and the cerebellum showed little or no change in catecholamine content, the hippocampus, striatum and brainstem all showed increases in noradrenaline and adrenaline. Additional analysis also showed that brainstem dopamine and 5-hydroxytryptamine levels (5-HT) increased as well. In vitro testing of sulfide for inhibition of monoamine oxidase (MAO) activity showed the anion to be inhibitory with an IC50 of 39.1 +/- 3.6 microM. Inhibition of MAO activity ex vivo could be demonstrated at a dose of 100 mg/kg but not at the lower dose of 30 mg/kg NaHS. Inhibition of enzyme activity could not be demonstrated at this lower dose, possibly due to the well known rapid intramitochondrial metabolism of sulfide. Correlation of synaptosomal and mitochondrial sulfide levels with enzyme inhibition data suggests that inhibition of MAO may be an important contributing factor to the mechanism(s) underlying loss of central respiratory drive after fatal intoxication with H2S.
In humans, urate is the final product of purine breakdown in the liver which releases urate into the circulation and the intestine and kidney regulate its excretion. Humans have a high circulating level of urate and small deviations are associated with a variety of metabolic diseases. A genome‐wide association scan correlated SNPs within the SLC2A9 gene, for the hexose transporter GLUT9, with hyperuricemia. This resulted in the identification of this protein as a high capacity urate transporter, which can exchange intracellular urate for extracellular glucose (1). Urate is an organic anion and voltage clamp experiments with GLUT9 expressed in Xenopus oocytes showed that its transport is electrogenic. Immunohistochemistry showed that all of the GLUT9 SNP mutants were expressed in the oocyte plasma membrane and flux studies indicate that all are functional. GLUT9 is expressed in the hepatocyte basolateral membrane and these data support the hypothesis that GLUT9 mediates the efflux of urate down its electrical gradient. Further, in the absence of direct functional effects of the SNPs, it appears that more complex effects of these mutations, perhaps on cytoskeletal interactions or yet to be identified regulatory mechanisms, affect the activity of GLUT9.1. Mark J. Caulfield, et al (2008) SLC2A9 is a high capacity urate transporter in man. PLoS Medicine 5(10):e197.Supported by the Canadian Breast Cancer Foundation.
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