The effect of chronic retrovirus infection and immune dysfunction on the P-450-mediated activation of acetaminophen in mouse liver microsomes.

Abstract

Acute viral infection has long been recognized to down-regulate cytochrome P-450 enzymes and subsequently to result in changes in the pharmacological and toxicological responses to xenobiotics. In our previous research, chronic retrovirus infection induced by inoculating a susceptible strain of mice with LP-BM5 murine leukaemia virus (MuLV) was found to suppress acetaminophen (APAP) induced liver injury. In the present study, we aimed to examine the influence of chronic retrovirus infection and its associated immune dysfunction on the activities of a number 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 as from age-matched controls were used in the study. The catalytic activities of the cytochrome P-450 isozymes 1A family and 2E1, catalysts for the activation of APAP, were measured in different microsomal preparations using O-dealkylation of alkoxyresorufin homologues and oxidation of p-nitrophenol, respectively, as the metabolic markers. The formation of the reactive APAP metabolite trapped as glutathione conjugate in the microsomal preparations was also determined. We demonstrated that there were variable changes in total hepatic P-450 levels and in the activities of a number of P-450 isozymes in animals with chronic retrovirus infection and immune dysfunction. Such changes seemed to be dependent on the stage of the disease and to have resulted in increases or minimal changes in the rate of APAP activation in hepatic microsomes collected from this animal model. This suggests that the P-450-mediated activation of APAP was not down-regulated in animals with chronic retrovirus infection. Enhanced elimination of APAP by detoxification metabolic pathways is more likely to be responsible for the increased resistance to APAP-induced hepatotoxicity observed in our previous research in animals with chronic retrovirus infection.