The duration of induction and species influences the downregulation of cytochrome P450 by the interferon inducer polyinosinic acid-polycytidylic acid

Interferon (IFN) has long been recognized to downregulate cytochrome P450-mediated drug metabolism. Some investigations have shown that induced P450 enzymes tend to be more resistant to the depressant effect of IFN, whereas constitutive forms of P450 are uniformly depressed by IFN. We examined the effect of varying the period of induction of P450 proteins (CYP1A1, CYP2B, and CYP2E1) in two animal species. In mice, the IFN inducer polyinosinic acid-polycytidylic acid depressed the constitutive and induced enzyme activities of ethoxyresorufin O-deethylase, benzyl-oxyresorufin O-dealkylase, and p-nitrophenol hydroxylase at all levels of induction. The depression of P450 proteins (CYP1A1, CYP2B10, and CYP2E1) was confirmed by immunoblotting. In contrast, the downregulation of the same enzyme activities observed at 0 and 24 hr of induction did not occur after 48 or 72 hr of induction in the rat. Immunoblotting confirmed that CYP1A1, CYP2B1, and CYP2E1 levels were downregulated in control and at low levels of induction, but were not affected at high levels of induction. The response of constitutive enzyme activities to downregulation by IFN was not influenced by any of the induction protocols in rats or mice. Thus, cytochrome P450 induction does not invariably confer resistance to IFN-mediated downregulation of the enzymes, and the mechanism of induction does not determine the response to IFN. It seems that the species and duration or level of induction are the major influences on the observed response of P450 enzymes to IFN-evoked downregulation.