Two distinct morphological patterns of cell death have been recognized, termed necrosis and apoptosis. Apoptosis, or programmed cell death, occurs in both physiological and pathological conditions. It arises due to an elevation of cytosolic free calcium concentration resulting in activation of a nuclear endonuclease. Activated endonuclease produces oligonucleosome-length DNA fragments. This DNA cleavage can directly precipitate cell death. Both glucocorticoids and TCDD may induce apoptosis by production of a heat labile factor that mediates calcium influx whereas tributyltin causes the opening of calcium channels. Evidence that perturbation in calcium homeostasis is an important event in cell necrosis is becoming increasingly persuasive, but the events that propagate the lesion are still unclear. Despite evidence for cytoskeletal disruption, activation of degradative enzymes such as proteases and phospholipase A2 and stimulation of other enzymes such as poly (ADP-ribose) polymerase, the exact role that these play in cell killing is not resolved. Indeed, recently the radical dichotomy between apoptosis and necrotic cell death has come into question. It is clear that further work is required to determine the role played by some elements of the apoptotic process in chemically induced cell death.

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Paracetamol is cytotoxic to hamster isolated hepatocytes by a mechanism that does not involve an early increase in [Ca2+]i. Although an increase in [Ca2+]i does occur, it accompanies rather than precedes, loss of viability. Studies with the ionophore, 4-bromo-A23187, suggest that although sustained elevations of [Ca2+]i per se can initiate cell death, this occurs at levels of [Ca2+]i only above 500 nM. This concentration was not achieved on exposure of cells to a cytotoxic concentration of paracetamol for 30 min. The [Ca2+]i-response of hepatocytes to vasopressin stimulation was not altered by exposing the cells to toxic concentrations of paracetamol. This demonstrates that paracetamol does not cause any impairment in the mobilisation or redistribution of Ca2+. The role of elevated levels of [Ca2+]i in mediating chemically-induced cell-killing requires re-evaluation.

The ability of iloprost (ZK36374) to protect hamster isolated hepatocytes from the toxic effects of paracetamol and its reactive metabolite N‐acetyl‐p‐benzoquinoneimine (NABQI) was investigated. The cytoprotection provided by iloprost was compared with that of N‐acetyl‐l‐cysteine. Treatment of hepatocytes with either NABQI (0.4 mm) or paracetamol (2 mm) alone resulted in a considerable loss of cell viability, as assessed by trypan blue exclusion or leakage of lactate dehydrogenase, accompanied by an increase in the percentage of viable cells that were blebbed. N‐acetyl‐l‐cysteine (1.25 mm) pretreatment diminished the loss of cell viability and the percentage of blebbed cells resulting from exposure to NABQI or paracetamol, whereas iloprost (10−16 m to 10−10 m) pretreatment reduced only the loss of cell viability, not the percentage of viable cells exhibiting blebbing. Pretreatment with N‐acetyl‐l‐cysteine significantly attenuated the depletion by paracetamol of glutathione and decreased the covalent binding of [14C]‐paracetamol to cellular proteins, whereas iloprost was without any such effects. The effects of iloprost and N‐acetyl‐l‐cysteine were also investigated by use of a model of paracetamol toxicity in which it is possible to study the biochemical events leading to cell injury separate from the generation of toxic metabolites. Hamster hepatocytes were incubated with paracetamol (4 mm) for 90 min at 37°C during which metabolism of paracetamol occurs with minimal loss of cell viability. Following washing of cells, to remove paracetamol and its metabolites, there was a progressive loss of viability and increase in the percentage of cells exhibiting blebbing when incubated in buffer alone. Addition of either N‐acetyl‐l‐cysteine (1.25 mm) or iloprost (10−14 m to 10−8 m), following washing, significantly reduced the expected loss of cell viability. Iloprost at concentrations outside this range was without effect. Paracetamol toxicity to isolated hepatocytes could be prevented or delayed by treatment with either N‐acetyl‐l‐cysteine or iloprost, but whereas the former prevented or even reversed plasma membrane blebbing with a resultant reduction in the percentage of viable cells that were blebbed, the prostanoid appeared only to delay the progression from plasma membrane blebbing to loss of viability. Hence, the percentage of viable cells that were ultimately blebbed following exposure to paracetamol was not significantly reduced by addition of iloprost. Aspirin or ibuprofen exacerbated the loss of viability induced by prior incubation with paracetamol. Thus, there may be a role for endogenous prostaglandins in protecting hepatocytes from paracetamol toxicity. Iloprost is cytoprotective without any effect upon toxin metabolism or detoxication. The mechanism of action of iloprost probably does not involve induction of prostaglandin synthesis or activation of the previously‐characterized prostacyclin receptor.