THE EFFECT OF CHRONIC RETROVIRUS INFECTION AND IMMUNE DYSFUNCTION ON THE P-450-MEDIATED ACTIVATION OF ACETAMINOPHEN IN MOUSE-LIVER MICROSOMES

Acute viral infection has long been recognized to down-regulate cytoch rome P-450 enzymes and subsequently to result in changes in the pharma cological and toxicological responses to xenobiotics. In our previous research, chronic retrovirus infection induced by inoculating a suscep tible strain of mice with LP-BM5 murine leukaemia virus (MuLV) was fou nd to suppress acetaminophen (APAP) induced liver injury. In the prese nt study, we aimed to examine the influence of chronic retrovirus infe ction and its associated immune dysfunction on the activities of a num ber of cytochrome P-450 isozymes and the P-450-mediated activation of APAP in mouse liver microsomes. Liver microsomes prepared from female C57BL/6 mice at 8 and 16 weeks after LP-BM5 MuLV inoculation as well a s from age-matched controls were used in the study. The catalytic acti vities of the cytochrome P-450 isozymes 1A family and 2E1, catalysts f or the activation of APAP, were measured in different microsomal prepa rations using O-dealkylation of alkoxyresorufin homologues and oxidati on of p-nitrophenol, respectively, as the metabolic markers. The forma tion of the reactive APAP metabolite trapped as glutathione conjugate in the microsomal preparations was also determined. We demonstrated th at there were variable changes in total hepatic P-450 levels and in th e activities of a number of P-450 isozymes in animals with chronic ret rovirus infection and immune dysfunction. Such changes seemed to be de pendent on the stage of the disease and to have resulted in increases or minimal changes in the rate of APAP activation in hepatic microsome s collected from this animal model. This suggests that the P-450-media ted activation of APAP was not down-regulated in animals with chronic retrovirus infection. Enhanced elimination of APAP by detoxification m etabolic pathways is more likely to be responsible for the increased r esistance to APAP-induced hepatotoxicity observed in our previous rese arch in animals with chronic retrovirus infection. (C) 1998 John Wiley & Sons, Ltd.