INFLUENCE OF DIET FREE OF NAD-PRECURSORS ON ACETAMINOPHEN HEPATOTOXICITY IN MICE

Recently, we demonstrated the hepatoprotective effects of nicotinic ac id amide, a selective inhibitor of poly(ADP ribose) polymerase (PARP; EC 2.4.2.30) on mice suffering from acetaminophen (AAP)-hepatitis, sug gesting that the AAP-induced liver injury involves a step which depend s on adenori-bosylation. The present study investigates the effects of a diet free of precursors of NAD, the substrate on which PARP acts, i n female NMRI mice with AAP hepatitis and evaluates the influence of s imultaneous ethanol consumption in these animals. Liver injuries were quantified as serum activities of glutamate-oxaloacetate transaminase (GOT) and glutamate pyruvate transaminase (GPT). While AAP caused a 11 7-fold elevation of serum transaminase activities in mice kept on a st andard laboratory diet, which was significantly exacerbated by ethanol and inhibited by nicotinic acid amide (NAA), adverse effects were not ed in animals fed a diet free of precursors of NAD. In these animals, only minor increases of serum transaminase activities were measured in the presence of AAP, and unlike the exacerbation caused by ethanol in mice on a standard diet, the liver damage was inhibited by 50% by eth anol. A further 64% reduction of hepatitis was observed, when NAA was given to ethanol/AAP-mice. Our results provide evidence that the AAP i nduced hepatitis and its exacerbation by ethanol can either be reduced by end product inhibition of PARP by NAA or by dietary depletion of t he enzyme's substrate NAD. We see the main application of NAA as for t he combinational use in pharmaceutical preparations of acetaminophen i n order to avoid hepatic damage in patients treated with this widely u sed analgesic.