Effects of immunomodulators on cytochrome P-450-dependent drug metabolizing enzyme activies

Abstract

Several types of interferons (IFNs) were tested for their ability to suppress TCDD-inducible cytochrome P-450(P-450)-dependent monooxygenase in primary mouse hepatocytes isolated from female B6C3F1, using EROD activity. Mouse IFN $_\gamma$ markedly suppressed EROD activity with time-and dose-dependency when added at the same time as TCDD, In contrast, mouse IFNα/β was only moderately suppressive. Rat IFN $_\gamma$ was even more suppressive than mouse; human IFN $_\gamma$ had no activity. Direct effects of mouse IFN $_\gamma$ was confirmed using a monoclonal antibody against to this IFN which blocked the action of mouse IFN $_\gamma$ and purified hepatocytes which were still sensitive to the effect of mouse IFN $_\gamma$. These results indicate that IFNs, particularly mouse and rat IF $_\gamma$, can antagonize TCDD-induced P-450 induction and IFNs has subtypes and species specificity in primary mouse hepatocyte cultures. Selective change in the isoformes of P-450 by mouse IFNγwas investigated. Mouse IFN $_\gamma$ markedly suppressed a TCDD or 3-MC-inducible EROD activity, which is speific for P-450IA1. in a dose-dependent manner. Suppression of P-450 isoformes by mouse IFN $_\gamma$ seems to be selective for TCDD-inducible EROD, as neither PB-inducible PROD and aminopyrine N-demethylase nor DEX-inducible erythromycin N-demethylase activities were affected. However, basal EROD and PROD activities were slightly suppressed but aminopyrine N-demethylase activity was not changed and erythromycin N-demethylase activity was increased by mouse IFN $_\gamma$. These results demonstrate that the effects of mouse IFN $_\gamma$ on the P450-dependent monooxygenase system are complex, involving differential regulation of several isoformes. Coincidely with above results, microsomal levels of TCDD-inducible P-450IA1 was decreased by mouse IFN $_\gamma$ but PB-inducible P-450IIB1/2 and DEX-inducible P-450IIIA1 were not changed in immunoblot analyses using monoclonal antibodies...