An investigation into the detoxification of microcystin-LR by the glutathione pathway in Balb/c mice.
Toxin-producing cyanobacteria pose a world-wide health threat to humans and animals due to their increasing presence in both drinking and recreational waters. The predominant cyanotoxin, microcystin-LR (MCLR), targets the liver and its toxicity depends on the uptake and removal rates in the liver. The role of the glutathione detoxification pathway in protecting the liver from the effects of MCLR was investigated. Mice exposed to a single 75% LD(50) dose of pure MCLR were sacrificed at 8, 16, 24 and 32 h post-exposure (pe). Toxin induced liver damage was observed 8 and 16 h pe as evidenced by raised serum ALT and LDH levels, reduced glycogen levels and liver histology. A significant increase in lipid peroxidation was seen at 16 h pe that decreased after 24 and 32 h pe, the time-points which showed significant increases in GPX activity. An increase in soluble GST activity was noted between 8 and 16 h pe, levels of total GSH increased at 24 h while oxidised glutathione increased throughout the investigation. The increase in activity of both GPX and GST corresponded with increased transcription of these enzymes, as well as the rate-limiting enzyme in GSH synthesis, gamma-glutamyl transferase. In conclusion, this study confirms that an increase in GST activity is critical for the detoxification of MCLR, that this is regulated at the transcriptional level, and that exposure to MCLR induces the de novo synthesis of GSH. Finally, we report the involvement of GPX in the removal of MCLR-induced lipid hydroperoxides.
Gehringer
Michelle M
MM
MRC/UCT Liver Research Centre, Groote Schuur Hospital, University of Cape Town, Old Main Building, Rondebosch, Cape Town, South Africa. mgehringer@unsw.edu.au
Shephard
Enid G
EG
Downing
Tim G
TG
Wiegand
Claudia
C
Neilan
Brett A
BA
D000818:Animals; D005260:Female; D015870:Gene Expression; D005978:Glutathione / Q000378:metabolism*; D005979:Glutathione Peroxidase / Q000187:drug effects / Q000378:metabolism; D005982:Glutathione Transferase / Q000187:drug effects / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D008658:Inactivation, Metabolic; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008387:Marine Toxins; D051379:Mice; D008807:Mice, Inbred BALB C; D052998:Microcystins; D020411:Oligonucleotide Array Sequence Analysis; D010456:Peptides, Cyclic / Q000493:pharmacokinetics / Q000633:toxicity*
D008387:Marine Toxins; D052998:Microcystins; D010456:Peptides, Cyclic; D006003:Glycogen; D005979:Glutathione Peroxidase; D005982:Glutathione Transferase; C057862:cyanoginosin LR; D005978:Glutathione