Interferon-Mediated Depression of Cytochrome P-450-Dependent Drug Biotransformation

A general property of interferon-inducing agents is depression of cytochrome P-450-dependent drug biotransformation in liver. Evidence for a direct involvement of interferon is suggested by experiments carried out in inbred strains of mice carrying four distinct genetic loci which influence the levels of circulating interferon produced by specific viruses. For Newcastle disease virus (NDV), one autosomal locus (IF-1) determines a 10-fold difference in serum interferon levels. We utilized strains of mice carrying the high (IF-1 h ) or low (IF-1 l ) production allele at the IF-1 locus to demonstrate that depression of hepatic cytochrome P-450 can be correlated with circulating interferon levels. In C57BL/6J mice containing the h-allele at IF-1, cytochrome P-450 and aminopyrine N-demethylase were decreased by 35% and 48%, respectively, 24 hr after the injection of NDV. The mean circulating level of interferon was 2443 PRD50 units/ml (PRD50 unit = amount of interferon required for 50% plaque reduction). In C3H/HeJ mice containing the l-allele at IF-1, no significant change was observed in cytochrome P-450 levels or in aminopyrine N-demethylase activities following injection of NDV. The circulating levels of interferon in this strain were below our lowest limits of detection. Poly(rI·rC), which induces interferon via loci other than IF-1, provided high levels of interferon and depressed cytochrome P-450 and aminopyrine N-demethylase in both strains of mice. It is concluded that an impairment of cytochrome P-450-dependent drug biotransformation can occur via an interferon-mediated interaction.