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Title: The mechanism of 2,3,5,6-tetramethyl-p-phenylenediamine myotoxicity in the rat : an in vivo and in vitro study
Author: Blair, Jeannette Ann
ISNI:       0000 0001 3466 986X
Awarding Body: University of London
Current Institution: University College London (University of London)
Date of Award: 2002
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2,3,5,6-TMPD, a derivative of p-phenylene diamine causes necrosis of skeletal muscle in a highly specific manner when administered to rats. The mechanism of TMPD toxicity in vivo is not fully understood. Previous research has revealed that the initiation site of TMPD toxicity is the mitochondrial respiratory chain protein, cytochrome c oxidase (complex IV), which catalyses the oxidation of the amine. Re-reduction of the di-imine metabolite by DT-diaphorase (NAD(P)H:quinone oxidoreductase) may facilitate a futile redox cycling reaction with concomitant depletion of reduced glutathione (GSH) and pyridine nucleotides. A single dose of TMPD (60 μmol kg-1) caused a reduction in glutathione (GSH) and ATP levels in the diaphragm. The effect was less pronounced in quadriceps muscle. These biochemical changes were accompanied by increases in serum transaminases and the skeletal muscle isoform of creatine kinase (CK-MM). Electron microscopy revealed gross damage to the mitochondria and sarcotubular elements of both diaphragm and quadriceps muscle. Oxidative fibres appeared to be more vulnerable to the toxic effects of TMPD than glycolytic fibres. This may reflect the metabolic differences and/or numbers of mitochondria that these muscles possess. Glutathione-S-transferase (GST) activity was increased in a dose-dependant manner, although glutathione reductase activity was inhibited by TMPD treatment. Superoxide dismutase (SOD) activity showed little change following exposure to the amine and correlated with evidence to suggest that oxidation of TMPD is not accompanied by significant oxygen activation. Cytotoxicity is believed to occur as a result of GSH depletion and the formation of mixed disulphides. Redox cycling of TMPD within the mitochondrion almost certainly contributes to the decrease in respiratory control and ADP:O ratios. This loss of function strongly correlates with the depletion of the mitochondrial GSH pool. Loss of the tripeptide would leave the thiol groups of the cell vulnerable to oxidative modification, which may explain the decrease in activity of the respiratory chain proteins, complex I, and complex II-III.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Pharmacology & pharmacy & pharmaceutical chemistry