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Metabolism of the carcinogen chromate by cellular constituents

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Inorganic Elements in Biochemistry

Part of the book series: Structure and Bonding ((STRUCTURE,volume 54))

Abstract

The redox chemistry of chromium(VI) is discussed with respect to the cellular metabolism of the carcinogen chromate in vivo. Possible sites for cellular reduction of chromium(VI) to chromium(III) are considered. The reactions of amino acids, ascorbic acid, carboxylic acids, thiol-containing mole-cules and other small molecules with chromate under physiological conditions are presented. In general only ascorbate and those molecules containing sulfhydryl groups are capable of easily reducing chromate at pH 7.4. Thus, in the cytoplasm, glutathione, cysteine and ascorbate are likely candidates to react with chromate. While most proteins are unreactive toward chromate, certain redox proteins are active in reducing chromate. The heme proteins hemoglobin and cytochrome P-450 possess chromate-reductase activity, whereas cytochrome c and myoglobin are inactive. The NADPH-dependent flavoenzymes glutathione reductase and NADPH-cytochrome P-450 reductase also possess chromate-reductase activity. However, the NAD(P)H enzymes, isocitrate dehydrogenase, glutamate dehyrogenase and malate dehydrogenase do not reduce chromate. Both microsomes and mitochondria possess chromate-reductase activity. The microsomal activity is accounted for by the NADPH-cytochrome P-450 reductase/cytochrome P-450 system. The enzyme(s) responsible for the mitochondrial reduction of chromate have not been identified. Chromium(VI) and its metabolite chromium(III) inhibit the normal activities of enzymes which bind chromium(III) or reduce chromate. The metabolism of chromate involves the generation of reactive intermediates which ultimately bind to cellular constituents and damage their function in the cell.

Postscript. Our continuing kinetic studies of thiol-chromate reactions (see Sect. 7) indicate that the logarithms of the observed rate constants (1 M Tris · HCl, pH 7.4, 25 °C) show an inverse linear relationship to the microscopic pKa’s of the thiols.

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Abbreviations

GSH:

glutathione (reduced form)

GSSG:

glutathione (oxidized form)

Cys:

cysteine

PSH:

penicillamine (reduced form)

PSSP:

penicillamine (oxidized form)

BAL:

2,3-dimercaptopropanol

Unithiol:

2,3-dimercapto-1-propane sulfonic acid

DTT:

dithiothreitol

NADH:

nicotinamide adenine dinucleotide (reduced form)

NAD+ :

nicotinamide adenine dinucleotide (oxidized form)

NADPH:

nicotinamide adenine dinucleotide phosphate (reduced form)

NADP+ :

nicotinamide adenine dinucleotide phosphate (oxidized form)

RBC:

red blood cell

Hb:

deoxyhemoglobin

Hb+ :

methemoglobin

Mb:

deoxymyoglobin

Mb+ :

metmyoglobin

GSSG-R:

glutathione reductase

Tris:

tris(hydroxymethyl)aminomethane

BP:

benzo[a]pyrene

ER:

endoplasmic reticulum

mt:

mitochondria

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  1. Department of Chemistry, Dartmouth College, 03755, Hanover, New Hampshire, USA

    Paul H. Connett & Karen E. Wetterhahn

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  1. Paul H. Connett
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Connett, P.H., Wetterhahn, K.E. (1983). Metabolism of the carcinogen chromate by cellular constituents. In: Inorganic Elements in Biochemistry. Structure and Bonding, vol 54. Springer, Berlin, Heidelberg. https://doi.org/10.1007/BFb0111319

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  • DOI: https://doi.org/10.1007/BFb0111319

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