Significance of apoptosis and its relationship to antioxidants after ochratoxin A administration in mice.
A study of the appearance of liver apoptosis after ochratoxin A (OTA) administration was performed in male mice. Administration of OTA twice a week for one or two weeks period results in the occurrence of apoptosis in mice"s liver. The presence of intracellular apoptosis bodies was detected at two weeks after toxin treatment. Light microscopic examination demonstrated the presence of eosinophilic globules, often containing apoptotic bodies. They were found within the cytoplasm of intact hepatic cells. The number of apoptotic bodies was further enhanced at two weeks, resulting in 8 fold increases in liver over the control values. No evidence of cell necrosis could be observed by histological and biochemical analysis at one week. However, centrilobular necrosis was evident at two weeks. The ability of the combined antioxidants: Coenzyme Q 10 (CoQ 10), L-carnitine, Zn, Mg, N-acetyl cysteine, vitamin C, vitamin E and selenium or tamoxifen to intervene in apoptosis induced in livers of mice by OTA was also investigated. The inhibition by these scavengers was more clear in mice treated with OTA for one week than those mice treated for two weeks. Treatment with tamoxifen, known in restoration of tumor suppressor function and on induction of programmed cell death (apoptosis), after OTA administration, had no significant inhibition effect on the incidence of apoptotic bodies in liver. Because hepatic glutathione represents the major defence against toxic liver injury, we studied the activity of tissue reduced glutathione (GSH), known to inhibit apoptosis. Our finding showed that two weeks after treatment, OTA caused a decrease of the GSH activity. However, treatment of mice with the combined antioxidants could enhance hepatic antioxidant/detoxification system, as indicated by increase in hepatic reduced glutathione level. In the light of these results, apoptosis was observed after two weeks of OTA administration. We also suggest that use of the combined antioxidants may be of interest in conditions were certain toxin-mediated forms of cell death and/or apoptosis contribute significantly to toxicity.
Atroshi
F
F
Department of Clinical Sciences, Pharmacology & Toxicology, Faculty of Veterinary Medicine, Helsinki University, Finland. faik.atroshi@helsinki.fi
Biese
I
I
Saloniemi
H
H
Ali-Vehmas
T
T
Saari
S
S
Rizzo
A
A
Veijalainen
P
P
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis; D002273:Carcinogens / Q000633:toxicity; D004347:Drug Interactions; D005978:Glutathione / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D009793:Ochratoxins / Q000633:toxicity*; D013629:Tamoxifen / Q000494:pharmacology
D016588:Anticarcinogenic Agents; D000975:Antioxidants; D002273:Carcinogens; D009793:Ochratoxins; D013629:Tamoxifen; C025589:ochratoxin A; D005978:Glutathione