Experimental paracetamol‐induced hepatic necrosis: A light‐and electron‐microscope, and histochemical study

Abstract

Rats were killed at various time-intervals up to 48 hr after a single large dose of paracetamol (3 g per kg) and their livers examined by light and electron microscopy. In general, this revealed glycogen depletion, loss of ribosomes, and cytoplasmic matrix swelling commencing 3-6 hr after administration which in centrilobular hepatocytes progressed to frank coagulative necrosis at 12-24 hr. Midzonal cells showed more prominent aqueous swelling with besiculation of the endoplasmic reticulum, and in some cells, gross hydropic vacuolation.

Impaired mitochondrial oxidative energy metabolism following paracetamol‐induced hepatotoxicity in the rat

“…These results have thus demonstrated, for the first time the effects of paracetamol toxicity at the level of organelle dysfunction. Disruption of the mitochondrial cristae and the transient increase in the succinate dehydrogenase activity followed by a decrease have been demonstrated by earlier workers with histological and histochemical techniques (Dixon et al, 1975;Dixon, 1984). The results of our present studies corroborate these reported observations.…”

“…Consequently, the serum transaminase levels were also found to be elevated (Dixon, 1984). Swelling of mitochondria, t) The Macmillan Press Ltd 1989 disruption of cristae and transient inconsistent increase in succinate dehydrogenase activity at 6h followed by a uniform loss in this enzyme activity have also been reported, based on histological and histochemical studies (Dixon et al, 1975;Dixon, 1984). However, there are few reports demonstrating the in vivo effects of paracetamol toxicity on cellular processes at biochemical levels.…”

“…In the U.S.A., the sale of this drug constitutes about 25% of the total analgesic sale over-the-counter (McClain, 1982). When used at normal therapeutic dose levels, it is considered to be a safe and an effective analgesic drug; however, at high doses this drug produces acute hepatotoxic and nephrotoxic effects, both in experimental animals and in man (Mitchell et al, 1973;Dixon et al, 1975;Hinson et al, 1981;Dixon, 1984). Massive hepatic centrilobular necrosis and acute renal failure are reported following paracetamol 1 Author for correspondence.…”

Reduced glutathione depletion causes necrosis and sensitization to tumor necrosis factor-α-induced apoptosis in cultured mouse hepatocytes

“…7,8 Careful descriptions of the pathology of APAP hepatotoxicity previously have noted the appearance of Councilman-like bodies in the midzone at the border of the centrilobular coagulative necrosis. 19 Furthermore, the participation of activated macrophages in the in vivo liver injury has been well documented over the past 15 years. 20,21 Indeed, various macrophage modulators protected against APAP.…”

“…Indeed, it is likely that the extent, timing, and duration of GSH depletion could account for conflicting results in the literature. 38 Although nuclear apoptosis-like changes have been observed in vivo in the liver of APAP-treated mice, [6][7][8]19 the above-cited inhibition of caspase activity 36 and the lack of difference in extent of liver injury in TNF-␣ knockout mice suggest that apoptosis may not be an important factor. 39 However, both of these studies employed a single, large dose of APAP.…”