@article {1213,
	title = {Dismutase activity of ADP-L-glycero-D-manno-heptose 6-epimerase: Evidence for a direct oxidation/reduction mechanism},
	journal = {Biochemistry},
	volume = {44},
	number = {15},
	year = {2005},
	note = {ISI Document Delivery No.: 916ZNTimes Cited: 11Cited Reference Count: 33},
	month = {Apr},
	pages = {5907-5915},
	type = {Article},
	abstract = {The first positive evidence for the utilization of a direct C-6" oxidation/reduction mechanism by ADP-L-glycero-D-manno-heptose 6-epimerase is reported here. The epimerase (HldD or AGME, formerly RfaD) operates in the biosynthetic pathway Of L-glycero-D-manno-heptose, which is a conserved sugar in the core region of lipopolysaccharide (LPS) of Gram-negative bacteria. The stereochemical inversion catalyzed by the epimerase is interesting as it occurs at an "unactivated" stereocenter that lacks an acidic C-H bond, and therefore, a direct deprotonation/reprotonation mechanism cannot be employed. Instead, the epimerase employs a transient oxidation strategy involving a tightly bound NADP(+) cofactor. A recent study ruled out mechanisms involving transient oxidation at C-4 {\textquoteright}{\textquoteright} and C-7 {\textquoteright}{\textquoteright} and supported a mechanism that involves an initial oxidation directly at the C-6 {\textquoteright}{\textquoteright} position to generate a 6"-keto intermediate (Read, J. A., Ahmed, R. A., Morrison, J. P., Coleman, W. G., Jr., Tanner, M. E. (2004) J. Am. Chem. Soc. 126, 8878-8879). A subsequent nonstereospecific reduction of the ketone intermediate can generate either epimer of the ADP-heptose. In this work, an intermediate analogue containing an aldehyde functionality at C-6 {\textquoteright}{\textquoteright}, ADP-beta-D-manno-hexodialdose, is prepared in order to probe the ability of the enzyme to catalyze redox chemistry at this position. It is found that incubation of the aldehyde with a catalytic amount of the epimerase leads to a dismutation process in which one-half of the material is oxidized to ADP-beta-D-mannuronic acid and the other half is reduced to ADP-beta-D-mannose. Transient reduction of the enzyme-bound NADP(+) was monitored by UV spectroscopy and implicates the cofactor{\textquoteright}s involvement during catalysis.},
	keywords = {ACID, ALCOHOL-DEHYDROGENASE, ALDEHYDE DEHYDROGENASE, D-MANNOHEPTOSE 6-EPIMERASE, DROSOPHILA-MELANOGASTER, EPIMERIZATION, ESCHERICHIA-COLI, GLUCOSE DEHYDROGENASE, LIVER, SITE RESIDUES, UDP-GALACTOSE 4-EPIMERASE},
	isbn = {0006-2960},
	url = {<Go to ISI>://000228425600037},
	author = {Morrison, J. P. and Read, J. A. and Coleman, W. G. and Tanner, M. E.}
}
@article {386,
	title = {Determination of arsenic metabolic complex excreted in human urine after administration of sodium 2,3-dimercapto-1-propane sulfonate},
	journal = {Chemical Research in Toxicology},
	volume = {15},
	number = {10},
	year = {2002},
	note = {ISI Document Delivery No.: 607TXTimes Cited: 15Cited Reference Count: 42},
	month = {Oct},
	pages = {1318-1323},
	type = {Article},
	abstract = {Sodium 2,3-dimercapto-1-propane sulfonate (DMPS) has been used to treat acute arsenic poisoning. Presumably DMPS functions by chelating some arsenic species to increase the excretion of arsenic from the body. However, the excreted complex of DMPS with arsenic has not been detected. Here we describe a DMPS complex with monomethylarsonous acid (MMA(III)), a key trivalent arsenic in the arsenic methylation process, and show the presence of the DMPS-MMA(III) complex in human urine after the administration of DMPS. The DMPS-MMA(III) complex was characterized using electrospray tandem mass spectrometry and determined by using HPLC separation with hydride generation atomic fluorescence detection (HGAFD). The DMPS-MMAIII complex did not form a volatile hydride with borohydride treatment. On-line digestion with 0.1 M sodium hydroxide following HPLC separation decomposed the DMPS-MMA(III) complex and allowed for the subsequent quantification by hydride generation atomic fluorescence. Arsenite (As-III), arsenate (As-V), monomethylarsonic, acid (MMA(V)), dimethylarsinic acid (DMA(V)), MMA(III), and DMPS-MMA(III) complex were analyzed in urine samples from human subjects collected after the ingestion of 300 mg of DMPS. The administration of DMPS resulted in a decrease of the DMA(V) concentration and an increase of the MMA(V) concentration excreted in the urine, confirming the previous results. The finding of the DMPS-MMA(III) complex in human urine after DMPS treatment provides an explanation for the inhibition of arsenic methylation by DMPS. Because MMA(III) is the substrate for the biomethylation of arsenic from MMA(V) to DMA(V), the formation of DMPS-MMA(III) complex would reduce the availability of MMA(III) for the subsequent biomethylation.},
	keywords = {ARSENICALS, CHALLENGE TEST, DRINKING-WATER, ENZYMATIC, GLUTATHIONE-REDUCTASE, HUMAN HEPATOCYTES, IN-VITRO INHIBITION, LIVER, METHYLATED, METHYLATION, MONOMETHYLARSONOUS ACID MMA(III), RABBIT, THIOREDOXIN REDUCTASE},
	isbn = {0893-228X},
	url = {<Go to ISI>://000178807800016},
	author = {Gong, Z. and Jiang, G. F. and Cullen, W. R. and Aposhian, H. V. and Le, X. C.}
}
@article {5130,
	title = {Arsenicals inhibit thioredoxin reductase in cultured rat hepatocytes},
	journal = {Chemical Research in Toxicology},
	volume = {14},
	number = {3},
	year = {2001},
	note = {ISI Document Delivery No.: 415LTTimes Cited: 86Cited Reference Count: 46},
	month = {Mar},
	pages = {305-311},
	type = {Article},
	abstract = {Thioredoxin reductase (TR), an NADPH-dependent flavoenzyme that catalyzes the reduction of many disulfide-containing substrates, plays an important role in the cellular response to oxidative stress. Trivalent arsenicals, especially methyl As that contains trivalent arsenic (MAsIII), are potent noncompetitive inhibitors of TR purified from mouse liver. Because MAsIII is produced in the biomethylation of As, it was postulated that the extent of inhibition of TR in cultured rat hepatocytes would correlate with the intracellular concentration of methyl As. Exposure of cultured hepatocytes to inorganic As-III (iAs(III)), MAsIII, or aurothioglucose (ATG, a competitive inhibitor of TR activity) for 30 min caused a concentration-dependent reduction in TR activity. The estimated IC50 was much greater than 100 muM for iAS(III), similar to 10 muM for ATG, and similar to3 muM for MAsIII. In hepatocytes exposed to 1 muM MAsIII for up to 24 h, the inhibition of TR activity was maximal (similar to 40\%) after exposure for 15 min. After exposure for 3 h [when most MAsIII has been converted to dimethyl As (DMAs)], TR activity in these cells had returned to control levels. Notably, exposure of the cell to 50 muM DMAsIII did not affect TR activity. In hepatocytes exposed to 10 muM iAs(III) for up to 24 h, the inhibition of TR activity was progressive; at 24 h, activity was reduced similar to 35\%. Following exposure to iAsIII or MAsIII, the extent of inhibition of TR activity correlated strongly with the intracellular concentration of MAs. Taken together, these results suggest that arsenicals formed in the course of cellular metabolism of As are potent inhibitors of TR activity. In particular, MAsIII, an intermediate in the metabolic pathway, is an especially potent inhibitor of TR. Hence, the capacity of cells to produce or consume the intermediates in the pathway for As methylation may be an important determinant of susceptibility to the toxic effects of As.},
	keywords = {apoptosis, ENZYMATIC REDUCTION, IN-VITRO METHYLATION, LIVER, MAMMALIAN SYSTEMS, MONOMETHYLARSONOUS ACID MMA(III), NF-KAPPA-B, RABBIT ERYTHROCYTES, REDOX, REGULATION, SUBSTRATE},
	isbn = {0893-228X},
	url = {<Go to ISI>://000167723600007},
	author = {Lin, S. and Del Razo, L. M. and Styblo, M. and Wang, C. Q. and Cullen, W. R. and Thomas, D. J.}
}
@article {4942,
	title = {Comparative toxicity of trivalent and pentavalent inorganic and methylated arsenicals in rat and human cells},
	journal = {Archives of Toxicology},
	volume = {74},
	number = {6},
	year = {2000},
	note = {ISI Document Delivery No.: 349ZATimes Cited: 358Cited Reference Count: 37},
	month = {Aug},
	pages = {289-299},
	type = {Article},
	abstract = {Biomethylation is considered a major detoxification pathway for inorganic arsenicals (iAs). According to the postulated metabolic scheme, the methylation of iAs yields methylated metabolites in which arsenic is present in both pentavalent and trivalent forms. Pentavalent mono- and dimethylated arsenicals are less acutely toxic than iAs. However, little is known about the toxicity of trivalent methylated species. In the work reported here the toxicities of iAs and trivalent and pentavalent methylated arsenicals were examined in cultured human cells derived from tissues that are considered a major site for iAs methylation (liver) or targets for carcinogenic effects associated with exposure to iAs (skin, urinary bladder, and lung). To characterize the role of methylation in the protection against toxicity of arsenicals, the capacities of cells to produce methylated metabolites were also examined. In addition to human cells, primary rat hepatocytes were used as methylating controls. Among the arsenicals examined, trivalent monomethylated species were the most cytotoxic in all cell types. Trivalent dimethylated arsenicals were at least as cytotoxic as trivalent iAs (arsenite) for most cell types. Pentavalent arsenicals were significantly less cytotoxic than their trivalent analogs. Among the cell types examined, primary rat hepatocytes exhibited the greatest methylation capacity for iAs followed by primary human hepatocytes, epidermal keratinocytes, and bronchial epithelial cells. Cells derived from human bladder did not methylate iAs. There was no apparent correlation between susceptibility of cells to arsenic toxicity and their capacity to methylate iAs. These results suggest that (1) trivalent methylated arsenicals, intermediary products of arsenic methylation, may significantly contribute to the adverse effects associated with exposure to iAs, and (2) high methylation capacity does not protect cells from the acute toxicity of trivalent arsenicals.},
	keywords = {ARSENATE, arsenic, ARSENITE, BINDING, bladder, cell culture, CELLULAR UPTAKE, DIMETHYLARSINIC ACID, dimethylarsinous acid, DRINKING-WATER, ENZYMATIC METHYLATION, GLUTATHIONE, HEPATOCYTES, HUMAN, IN-VITRO METHYLATION, LIVER, lung, METABOLISM, methylarsonic acid, methylarsonous acid, METHYLATION, RABBIT LIVER, SKIN, TOXICITY},
	isbn = {0340-5761},
	url = {<Go to ISI>://000089074500001},
	author = {Styblo, M. and Del Razo, L. M. and Vega, L. and Germolec, D. R. and LeCluyse, E. L. and Hamilton, G. A. and Reed, W. and Wang, C. and Cullen, W. R. and Thomas, D. J.}
}
@article {4901,
	title = {Monomethylarsonous acid (MMA(III)) is more toxic than arsenite in Chang human hepatocytes},
	journal = {Toxicology and Applied Pharmacology},
	volume = {163},
	number = {2},
	year = {2000},
	note = {ISI Document Delivery No.: 295TBTimes Cited: 294Cited Reference Count: 28},
	month = {Mar},
	pages = {203-207},
	type = {Article},
	abstract = {Methylation has been considered to be the primary detoxication pathway of inorganic arsenic. Inorganic arsenic is methylated by many, but not all animal species, to monomethylarsonic acid (MMA(V)), monomethylarsonous acid (MMA(III)), and dimethylarsinic acid (DMA(V)). The As-V derivatives have been assumed to produce low toxicity, but the relative toxicity of MMA(III) remains unknown. In vitro toxicities of arsenate, arsenite, MMA(V), MMA(III) and DMA(V) were determined in Chang human hepatocytes, Leakage of lactate dehydrogenase (LDH) and intracellular potassium (K+) and mitochondrial metabolism of the tetrazolium salt XTT were used to assess cytotoxicity due to arsenic exposure. The mean LC50 based on LDH assays in phosphate media was 6 mu M for MMA(III) and 68 mu M for arsenite. Using the assay for K+ leakage in phosphate media, the mean LC50 was 6.3 mu M for MMA(III) and 19.8 mu M for arsenite. The mean LC50 based on the XTT assay in phosphate media was 13.6 mu M for MMA(III) and 164 mu M for arsenite. The results of the three cytotoxicity assays (LDH, K+, and XTT) reveal the following order of toxicity in Chang human hepatocytes: MMA(III) > arsenite > arsenate > MMA(V) = DMA(V). Data demonstrate that MMA(III) an intermediate in inorganic arsenic methylation, is highly toxic and again raises the question as to whether methylation of inorganic arsenic is a detoxication process. (C) 2000 Academic Press.},
	keywords = {ARSENATE, ARSENITE, ASSAY, CELLS, Chang human hepatocytes, DIMETHYLARSINIC ACID, DMA, DMA(V), DMPS, ENZYMATIC METHYLATION, LDH, LIVER, MICE, MMA(III), MMA(V), monomethylarsonic acid, MONOMETHYLARSONOUS ACID, POTASSIUM, VIABILITY, XTT},
	isbn = {0041-008X},
	url = {<Go to ISI>://000085983000013},
	author = {Petrick, J. S. and Ayala-Fierro, F. and Cullen, W. R. and Carter, D. E. and Aposhian, H. V.}
}
@article {4673,
	title = {Metabolism of arsenic in primary cultures of human and rat hepatocytes},
	journal = {Chemical Research in Toxicology},
	volume = {12},
	number = {7},
	year = {1999},
	note = {ISI Document Delivery No.: 219JCTimes Cited: 81Cited Reference Count: 26},
	month = {Jul},
	pages = {560-565},
	type = {Article},
	abstract = {The liver is considered a major site for methylation of inorganic arsenic (iAs). However, there is Little data on the capacity of human liver to methylate iAs. This work examined the metabolism of arsenite (iAs(III)), arsenate (iAs(v)), methylarsine oxide ((MAsO)-O-III), methylarsonic acid (MAsv), dimethylarsinous acid (DMAsIII), and dimethylarsinic acid (DMAsV) in primary cultures of normal human hepatocytes. Primary rat hepatocytes were used as methylating controls, iAs(III) and (MAsO)-O-III were metabolized more extensively than iAs(v) and MAsv by either cell type. Neither human nor rat hepatocytes metabolized DMAsIII or DMAsV. Methylation of iAs(III) by human hepatocytes yielded methylarsenic (MAs) and dimethylarsenic (DMAs) species; (MAsO)-O-III was converted to DMAs. The total methylation yield (MAs and DMAs) increased over the range of 0.1 to 4 mu M iAs(III). However, DMAs production was inhibited by iAs(III) in a concentration-dependent manner, and the DMAs/MAs ratio decreased. iAs(III) (10 and 20 mu M) inhibited both methylation reactions. Inhibition of DMAs synthesis resulted in accumulation of iAs and MAs in human hepatocytes, suggesting that dimethylation is required for iAs clearance from cells. Methylation capacities of human hepatocytes obtained from four donors ranged from 3.1 to 35.7 pmol of iAs(III) per 10(6) cells per hour and were substantially lower than the methylation capacity of rat hepatocytes (387 pmol of iAs(III) per 10(6) cells per hour). The maximal methylation rates for either rat or human hepatocytes were attained between 0.4 and 4 mu M iAs(III). In summary, (i) human hepatocytes methylate iAs, (ii) the capacities for iAs methylation vary among individuals and are saturable, and (iii) moderate concentrations of iAs inhibit DMAs synthesis, resulting in an accumulation of iAs and MAs in cells.},
	keywords = {ASSAY, ENZYMATIC METHYLATION, IN-VITRO, INGESTION, LIVER, PURIFICATION, TOXICITY, URINARY-EXCRETION},
	isbn = {0893-228X},
	url = {<Go to ISI>://000081603300003},
	author = {Styblo, M. and Del Razo, L. M. and LeCluyse, E. L. and Hamilton, G. A. and Wang, C. Q. and Cullen, W. R. and Thomas, D. J.}
}
@article {3114,
	title = {IN-VIVO INHIBITION OF BETA-GLUCOSIDASE AND BETA-MANNOSIDASE ACTIVITY IN RATS BY 2-DEOXY-2-FLUORO-BETA-GLYCOSYL FLUORIDES AND RECOVERY OF ACTIVITY IN-VIVO AND IN-VITRO},
	journal = {Biochemical Journal},
	volume = {301},
	year = {1994},
	note = {ISI Document Delivery No.: PA559Times Cited: 12Cited Reference Count: 25Part 2},
	month = {Jul},
	pages = {343-348},
	type = {Article},
	abstract = {2-Deoxy-2-fluoro-beta-glucosyl and -beta-mannosyl fluorides administered to rats in a single dose(10 mg/kg) inhibited beta-glucosidase and beta-mannosidase activity respectively after 1 h in brain, spleen, liver and kidney tissues. This inhibition, presumably caused by accumulation of 2-deoxy-2-fluoroglycosyl-enzyme intermediates, indicates that intact 2-deoxy-2-fluoroglycosyl fluorides are distributed to these organs and, in the case of brain, that they cross the blood/brain barrier. beta-Glucosidase activity recovered completely or partially in brain, spleen, liver and kidney by 20-48 h. beta-Mannosidase activity partially recovered in all tissues by 48 h. beta-Galactosidase activity in brain and kidney was not significantly affected by administration of either the gluco or manno compounds at this dosage, indicating that these inhibitors are directed towards specific glycosidases. Observation of similar relatively rapid rates of beta-glycosidase re-activation in vivo and in tissue homogenates in vitro at 37 degrees C suggests that hydrolysis or transglycosylation of 2-deoxy-2-fluoroglycosyl-enzymes, not protein synthesis, are the primary mechanisms involved in the recovery of glycosidase activity inhibited by this class of compounds in vivo.},
	keywords = {DEFICIENCY, ENZYME INTERMEDIATE, FORMS, GLUCOCEREBROSIDASE, GLYCOSIDASES, INACTIVATION, LIVER, MICE},
	isbn = {0264-6021},
	url = {<Go to ISI>://A1994PA55900006},
	author = {McCarter, J. D. and Adam,Michael J. and Hartman, N. G. and Withers, S. G.}
}
