Benzo[a]pyrene: kinetics of in vitro bioactivation in relation to inhibition of viral interferon induction.

Abstract

The kinetics of benzo[a]pyrene (BaP) bioactivation by rat liver S9 fraction was characterized on the basis of inhibition of influenza virus induction of interferon-alpha/beta (IFN-alpha/beta) in mammalian LLC-MK2 cell cultures. Both viral IFN induction and production phases were sensitive to the adverse effects of bioactivated BaP. The integral role of S9 for BaP bioactivation and the resultant inhibition of viral IFN induction was substantiated by dose-response relationships, time-dependency of effects, and reversibility of adverse reactivity. When preceded by the analog, benzo[e]pyrene (BeP), the inhibitive action of bioactivated BaP on IFN induction was abrogated. That the ability of exogenous IFN to confer antiviral cellular resistance was unaffected by bioactivated BaP indicates that neither requisite cellular protein nor enzyme syntheses were impaired. In cells pretreated with bioactivated BaP, influenza virus multiplication reached a level that was more than twofold higher than in normal cells which was a reflection of decreased IFN production. These findings further imply that neither virus inducer-cell interactions (attachment and penetration) nor requisite viral protein and RNA syntheses were affected appreciably. BaP was selectively cyto-antagonistic to critical inducer-processing phases of IFN induction. Of 32 different mammalian cell cultures tested for indigenous metabolizing enzyme-bioactivation of BaP, based on approximately equal to 50% resultant inhibition of IFN induction, only 37.5% were responsive.