Suppression of P450IIC12 gene expression and elevation of actin messenger ribonucleic acid levels in the livers of female rats after injection of the interferon inducer poly rI·poly rC

Abstract

Interferons and interferon inducers cause a reduction in hepatic microsomal cytochrome P450 [AH, reduced-flavoprotein:oxygen oxidoreductase (RH hydroxylating), EC 1.14.14.1] content and drug-metabolizing activities in experimental animals. In the present study, the acute effects of administration of the interferon inducer polyriboinosinic acid · polyribocytidylic acid (poly rI·polyrC) to female rats on expression of the microsomal apoprotein and hepatic mRNA for P450IIC12, a constitutive enzyme comprising a significant fraction of the total P450 in untreated female rats, were examined. Poly rI·poly rC treatment (10mg/kg, i.p.) caused a suppression of P450IIC12 apoprotein that was of greatest magnitude (47% of control levels) 24 hr after injection. P450IIC12 was still suppressed significantly (P<0.05) 48 hr after treatment. The time course of suppression and recovery of P450IIC12 protein, as well as the magnitude of the effect, were similar to those of total microsomal P450 measured spectrophotometrically. P450IIC12 mRNA levels were also suppressed by the poly rI·poly rC treatment, reaching 29% of control values within 24 hr. Comparison of the kinetics of suppression of the P450IIC12 mRNA and apoprotein indicated that at least part of the suppression of the protein is mediated pretranslationally. However, the existence of a posttranslational component could not be excluded. Concomitant with the suppression of P450IIC12, actin mRNA content was found to be elevated by at least 3.6-fold in the livers of poly rI·poly rC-treated female rats, with the maximum effect occuring 12 hr after injection of the drug. This effect of poly rI·poly rC on expression of actin mRNA appeared to be at least partially sex-specific, since in a previous study [Morgan ET and Norman CA, Drug Metab Dispos 18: 649–653, 1990] a significant effect of the interferon inducer on actin expression was not observed in livers of male rats.