Experimental acetaminophen-induced hepatic necrosis: biochemical and electron microscopic study of cysteamine protection.

In an attempt to elucidate the biochemical mechanism of acetaminophen-induced hepatic necrosis, the present study in hamsters was undertaken to evaluate the possible changes in lipid peroxidation and microsomal enzyme activities. The protective action of cysteamine was likewise assessed in the light of these biochemical variables and the fine structural features of the liver were seen by electron microscopy. One group of golden Syrian hamsters was administered a toxic dosage of acetaminophen (600 mg . per kg . intraperitoneally) while another group was treated with the same dosage of acetaminophen, followed 1 hour later by cysteamine (200 mg . per kg . intraperitoneally). The animals were sacrificed at 6, 12, 18, and 24 hours. Microsomal fractions were isolated for biochemical assays, and liver sections were prepared for electron microscopy. Results showed that significant enhancement of lipid peroxidation occurred in the untreated acetaminophen-poisoned group, as compared to the cysteamine-treated group. Glucose 6-phosphatase activity was markedly suppressed at 6, 12, and 18 hours after acetaminophen administration. Cysteamine treatment completely prevented the curtailment of NADPH-cytochrome c reductase and glucose 6-phosphatase activities in the protected group, and partially maintained aniline hydroxylase activity. Cytochrome P-450 level was unaffected in both the cysteamine-treated and the untreated groups at the respective time intervals. Electron microscopic examination showed progressive loss of the structural integrity of the endoplasmic reticulum, lipid infiltration, and vacuolation in the untreated acetaminophen-poisoned group. At 18 and 24 hours, sinusoidal congestion and myeloid figure formation were prominent. In the cysteamine-protected group, polysomes reassembled around the granular endoplasmic reticulum at 18 hours. It is postulated that lipid peroxide formed in vivo may facilitate the microsomal oxidation of acetaminophen to the toxic metabolite. NADPH-cytochrome c reductase is likely to be the locus within the NADPH-cytochrome P-450 electron transport chain susceptible to lipoperoxidation. The free radical-related lipoperoxidation may mediate the impairment of in vitro drug metabolism, as reflected by the depressed aniline hydroxylase activity. The abnormal phospholipid metabolism is manifested at the fine structural level by the myeloid body formation. The protective effects of cysteamine as seen in the attenuated lipid peroxidation and the consequent derangement of microsomal enzymes correlate well with the morphologic observations. Cysteamine protection is discussed in terms of its role as an inhibitor of the toxic metabolite formation.