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Hepatotoxicity of microcystin-LR in fed and fasted rats
G A Miura1, N A Robinson, W B Lawrence
1Pathophysiology Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, MD 21702-5011.
Abstract:
The LD50 (25 hr, i.p.) for microcystin-LR in fed rats (122 micrograms/kg) was significantly higher than that in fasted rats (72 micrograms/kg). At doses of 100, 150 and 200 micrograms of microcystin-LR per kg, the median times to death were 31.9, 18.2 and 11.2 hr for fed rats, and 1.8, 1.7 and 1.5 hr for fasted rats. A sublethal dose of microcystin (50 micrograms/kg) afforded protection to fasted, but not fed, rats against a subsequent lethal dose (200 micrograms/kg) challenge given 72 hr later. Biochemical and ultrastructural changes resulting from microcystin-LR (100 micrograms/kg, i.p.) were compared in fed and fasted rats 1 hr after injection. In both groups, liver weight and serum levels of sorbitol dehydrogenase and glucose significantly increased. Plasma membranes, isolated from livers of fed or fasted rats, exhibited similar toxin-induced changes in associated cytoskeletal elements. Liver mitochondria from toxin-treated, fasted rats exhibited complete inhibition of state 3 respiration, while those from toxin-treated, fed rats had ADP/O ratios and respiratory control indices comparable to control values. The primary event responsible for enhanced microcystin hepatotoxicity in the fasted state has not yet been identified. Depletion of glycogen stores and a decreased respiratory capacity may, however, play significant roles in this degenerative process.
Insights
Fasting significantly increases microcystin-LR toxicity in rats, lowering the median lethal dose and time to death. This enhanced toxicity in fasted rats may be linked to depleted glycogen and reduced mitochondrial respiratory capacity.
Area of Science:
- Toxicology
- Hepatotoxicity
- Environmental Health
Background:
- Microcystin-LR is a potent hepatotoxin produced by cyanobacteria.
- Factors influencing microcystin toxicity, such as nutritional status, are not fully understood.
Purpose of the Study:
- To investigate the impact of fasting on microcystin-LR toxicity and associated biochemical changes in rats.
- To compare the effects of microcystin-LR in fed versus fasted animal models.
Main Methods:
- Determined LD50 (median lethal dose) and median times to death in fed and fasted rats following intraperitoneal injection of microcystin-LR.
- Administered sublethal and lethal doses to assess protection and toxicity.
- Analyzed biochemical markers (liver weight, serum enzymes, glucose) and mitochondrial respiration in liver tissues.
Main Results:
- Fasted rats exhibited significantly lower LD50 and shorter median times to death compared to fed rats.
- A sublethal dose protected fasted rats but not fed rats against subsequent lethal challenge.
- Microcystin-LR increased liver weight and serum sorbitol dehydrogenase and glucose in both groups.
- Mitochondria from fasted rats showed complete inhibition of state 3 respiration, unlike fed rats.
Conclusions:
- Fasting markedly enhances microcystin-LR hepatotoxicity in rats.
- Reduced mitochondrial respiratory capacity in fasted rats is a key factor in increased toxicity.
- Glycogen depletion and decreased respiratory function may contribute to microcystin-LR's enhanced toxicity in the fasted state.