The cytochrome P450 enzyme system is important in the metabolism of many endo- and xenobiotic agents, including many therapeutic drugs. We and others have demonstrated that the acute, LPS-induced inflammatory response and its associated cytokines playa role in the modulation of cytochrome P450. This report describes the effects of murine retrovirus LP-BM5 infection on total P450 and P450 form-dependent metabolic activities in mouse hepatic microsomes. Mice were inoculated with a mixture of LPBM5 and sacrificed at 2, 4, 6, 8, 14 and 20 weeks post-infection to evaluate the effect of infection and progression to MAIDS on total P450, p-nitrophenol hydroxylase (PNP) and the dealkyation of benzyloxy-, ethoxy- and pentoxyresorufins (BROD, EROD and PROD) in hepatic microsomes. The expression of mRNA coding for the cytokines, interferon (IFN), interleukins 1 and to (IL 1 and IL 10) and TGF was also examined in lung. Infection of mice with LP-BM5 produced a slight decreases in total P450 at 2 weeks postinfection, these minor losses were seen in all the activities examined. Total P450 and associated activities were not further altered until week 20; while EROD remained at 70% of controls, BROD, PROD and PNP in infected animals were only 40% of the control values. Lung-mRNAs for IFN, IL-I, 1L-10 and TGF all increased after infection and peaked by week 8. TGF and IL-10 remained elevated out to week 20; ILl and IFN slowly declined after week 8. This report describes the effect of MAIDS on hepatic P450 and its associated activities. If similar responses occur in humans with AIDS, careful monitoring of the efficacy and safety of administered drugs is warranted.
The Toxicologist. Society of Toxicology 36th Annual Meeting, March 9-13, 2006, Cincinnati, Ohio