Mechanistic study on formaldehyde-induced hepatotoxicity.
In isolated, hemoglobin-free perfused livers of fasted rats, formaldehyde at an initial concentration of 10 mmol/l produced toxicity as evidenced by a release of enzymes (GPT, SDH) and of glutathione (mainly GSSG) into the perfusate, an accumulation of calcium in the liver, and a depletion of hepatic glutathione. Formaldehyde also led to an enhanced release of malondialdehyde into the perfusate, indicating peroxidative processes and decreased hepatic oxygen consumption by about 50-70%. The electron microscopic investigation of formaldehyde-exposed livers showed a destruction of the mitochondria (ruptured membranes, loss of the cristae) and some damage of the rough endoplasmic reticulum. Feeding the rats prior to surgery attenuated the hepatotoxic effects of 10 mmol/l formaldehyde. At an initial concentration of 3 mmol/l, formaldehyde did not release enzymes from livers of fed or fasted rats but only from those whose glutathione content had been depleted by treatment with phorone (250 mg/kg ip 2 h earlier). Formaldehyde liberated glucose and lactate from the livers of fed but not from those of fasted rats, indicating anaerobic energy supply in the fed state. The hepatotoxic action of formaldehyde is not due to its metabolism to formate or to the 10% methanol added as a stabilizing agent to the commercially available 37% solution named formalin. In conclusion, by destruction of mitochondria, formaldehyde inhibits aerobic energy supply and thereby presumably produces hepatocellular damage.
Institut für Toxikologie, Medizinische Universität zu Lübeck, Federal Republic of Germany.
O
O
Strubelt
M
M
Younes
R
R
Pentz
W
W
Kühnel
D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D005557:Formaldehyde / Q000633:toxicity*; D005978:Glutathione / Q000378:metabolism; D066298:In Vitro Techniques; D007064:L-Iditol 2-Dehydrogenase / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000473:pathology* / Q000648:ultrastructure; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D008854:Microscopy, Electron; D010101:Oxygen Consumption / Q000187:drug effects; D010477:Perfusion; D051381:Rats; D011919:Rats, Inbred Strains
D005557:Formaldehyde; D008315:Malondialdehyde; D007064:L-Iditol 2-Dehydrogenase; D007770:L-Lactate Dehydrogenase; D000410:Alanine Transaminase; D005978:Glutathione; D002118:Calcium