P450 enzymes metabolize many drugs, toxins, and endogenous compounds in all organ systems. Cytokines and nitric oxide decrease P450 function in human hepatocyte culture. In humans, endotoxin administration increased the half-life (t_(1/2)) of antipyrine, a standard measure of P450 function. Previously, we showed that inflammation as indicated by plasma levels of IL-6 and nitrite + nitrate levels (end products of nitric oxide metabolism) is increased in children with sepsis-induced multiple organ failure(MOF).(1) The relationship between P450 function, inflammation, and the development of multiple organ failure in children with sepsis is unknown. We hypothesize that in sepsis-induced MOF, P450 function will be decreased and will be associated with the degree of inflammation. Plasma IL-6 (ELISA) and nitrite + nitrate (Greiss reaction) and an organ failure index (OFI, 1 point for each organ failure)^(1) were determined in 33 children on days 1-3 of sepsis. On day 1, antipyrine(18mg/kg) was administered (ng/po) and levels were measured by HPLC at 6, 12, 24, and 48 hours to calculate antipyrine t_(1/2) (normal t_(1/2) = 8± 2 hours). Definitions were: persistent MOF (OFI ≥ 3 on day 3), resolved MOF(OFI ≥ 3 on day 1 or 2 but < 3 by day 3), or no MOF (OFI < 3). Children with hepatic failure (n=4) were excluded to correlate antipyrine t_(1/2), inflammation, and organ failure. Antipyrine t_(1/2) ranged from 8 to 107 hours and was greatest in persistent MOF (n=10, 49 ± 11 hours*) compared to resolved MOF (n=7, 33 ± 9 hours) and no MOF (n=16, 19± 2 hours) (* p<.05 Kruskall Wallis with Dunn's test for persistent MOF vs no MOF). Persistent MOF was more prevalent when antipyrine t_(1/2) was> 20 hours (normal t_(1/2) ± 6SD) compared to < 20 hours (9of 20 vs 1 of 13, p<.05 Fisher's Exact). Antipyrine t_(1/2) correlated with the plasma IL-6 levels (day 2 r_ (s) =.43, day 3 r_ (s) =.5), nitrite+nitrate levels (day 2 r_ (s) =.4, day 3 r_ (s) =.48), and OFI (day 2 r_ (s) =.46, day 3 r_ (s) =.46) (p<.05). P450 function is decreased in sepsis-induced persistent MOF and is associated with inflammatory cytokines and nitric oxide. Our study supports rigorous monitoring of P450 metabolized drugs during sepsis and MOF. Future study is necessary to determine the impact of decreased P450 function in sepsis-induced MOF.
