INCREASED RESISTANCE TO ACETAMINOPHEN-INDUCED HEPATOTOXICITY IN RETROVIRUS-INFECTED MICE

In this research we examined the influence of chronic retrovirus infec tion on the hepatic metabolism of a model substrate, acetaminophen (AP AP), and its induced liver injury in mice inoculated with LP-BM5 murin e leukemia viruses. Female C57BL/6 mice at 15-17 wks after LP-BM5 retr ovirus inoculation and age-matched control animals were used in the st udies. APAP treatment (300 mg kg(-1), p.o.) resulted in moderate to se vere centrilobular necrosis in control animals, with the necrotic area accounting for 40-60% of the total area. In contrast, the APAP-treate d (300 mg kg(-1), p.o.) infected animals exhibited mild zonal necrosis with the necrotic area accounting for 1-6% of the total area. In the same study, a statistically significant higher percentage of APAP gluc uronide and a lower percentage of unchanged APAP were recovered from t he urine of the LP-BM5-inoculated animals than from that of controls. No statistically significant differences between infected and uninfect ed animals in the urinary recovery of APAP sulfate, APAP cysteine, or APAP mercapturate were observed. The formation of APAP metabolites and APAP-associated biochemical changes were also determined from liver s lice preparation to avoid in vivo complicating factors. Consistently m ore significant depletion of the intracellular glutathione levels and K+ content were observed in slices from the uninfected animals at high concentrations of APAP (1 and 2 mM) than in slices from the retroviru s-infected animals. The differences in APAP-associated biochemical cha nges were accompanied by a 1.4-1.5-fold increase in the formation of A PAP glucuronide, sulfate, and glutathione metabolites in slices prepar ed from animals inoculated with LP-BM5. We concluded that, based on hi stological examination and hepatic biochemical measurements, the retro virus-infected animals were more resistant to APAP-induced liver injur y. This could be due, in part, to alterations in the detoxification an d activation metabolic pathways of APAP.