Electron transport and protection of liver slices in the late stage of paracetamol injury.
Cell injury by chemicals takes place in two stages, initial chemical interaction between the material and cell components, and subsequent stages of adaptation or failure of response to chemical modification of some parts of the cell apparatus. Paracetamol toxicity was studied in an in vitro system using liver slices incubated in two stages. During the first 2 hr slices were exposed to 10 mM paracetamol and this was absent during the following 4 hr of incubation. Damage was quantified at the end by measuring leakage of lactate dehydrogenase (LDH), increase in water content and potassium loss. Treatment of slices with 10 microM DCPIP or 2 mM ethanol in the second period of incubation prevented paracetamol-induced damage. The protective effect was not dependent on the activity of P450 since the second stage of incubation was insensitive to SKF-525A. The protective effect of ethanol was blocked by the presence of 1 mM pyrazole suggesting that ethanol needs to be metabolized to exert its effect. The addition of 20 mM pyruvate reversed the protection provided by ethanol. Nicotinamide did not alter toxicity or protection by ethanol. These findings suggest an increase of NADH and NADH/NAD ratio as the most probable explanation for the protective effect observed. The role of reducing equivalents in detoxification of quinones such as NAPQI by formation of hydroquinones, is discussed in relation to the mechanism of cell injury by paracetamol.
Mourelle
M
M
Department of Clinical Pharmacology, University College London, U.K.
Beales
D
D
McLean
A E
AE
D015086:2,6-Dichloroindophenol / Q000494:pharmacology*; D000082:Acetaminophen / Q000633:toxicity*; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D004579:Electron Transport / Q000187:drug effects; D000431:Ethanol / Q000494:pharmacology*; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D013997:Time Factors
D000082:Acetaminophen; D000431:Ethanol; D015086:2,6-Dichloroindophenol