PERTUSSIS TOXIN-INDUCED ALTERATIONS OF MURINE HEPATIC DRUG-METABOLISMFOLLOWING ADMINISTRATION OF DIPHTHERIA AND TETANUS TOXOIDS AND PERTUSSIS-VACCINE ADSORBED

Administration of pertussis toxin (PT) in combination with diphtheria and tetanus toxoids adsorbed (DT vaccine) or with acellular pertussis vaccine adsorbed and diphtheria and tetanus toxoids (APDT) elicits dos e- and time-dependent alterations in hepatic drug metabolism in mice. Cytochrome P-450 (P-450) levels were inhibited more than 50% at 7 days following a single injection of PT mixed with either vaccine. When co mbined with DT vaccine, 125 ng of PT was required to produce this effe ct, while as little as 16 ng of PT combined with APDT vaccine inhibite d P-450 levels. The inhibition of P450 levels is similar to that obser ved after a single injection of diphtheria and tetanus toxoids and per tussis vaccine adsorbed (DTP). Alterations of P-450 levels were accomp anied by increased activities of quinone reductase but not with change s in plasma interleukin-6 or tumor necrosis factor levels. Other Borde tella pertussis virulence factors, such as filamentous hemagglutinin, fimbriae and pertactin, were also tested but had no significant effect on hepatic drug metabolism. Endotoxin or preparations containing endo toxin caused alterations in hepatic drug metabolism within 24 h, conco mitant with increased interleukin-6 and tumor necrosis factor levels, but these effects had resolved by 1 week. DTP vaccine and preparations containing PT caused a marked induction of gamma interferon coinciden t with the maximal inhibition of P-450 levels. This effect was not pre sent with DT or APDT vaccine alone, nor with endotoxin or any combinat ion of factors that did not contain PT. These results demonstrate that PT is a necessary component for the sustained effects of DTP vaccine on hepatic drug metabolism and suggest a role for gamma interferon in this process.