Biotransformation of paraoxon and p-nitrophenol by isolated perfused mouse livers

Single-pass perfusion in situ of mouse livers with the organophosphate paraoxon resulted in formation of p-nitrophenol (PNP), p-nitrophenyl sulfate (PNPS), and p-nitrophenyl-β-D-glucuronide (PNPG). Following initiation of perfusion of paraoxon steady-state conditions were achieved in 15-25 min, at which time the extraction ratio was 0.55 (S.D. = 0.05). This suggests the capacity of mouse liver to biotransform paraoxon is not as great as previously reported. At all concentrations of paraoxon examined the amount of PNPS produced exceeded that of PNPG. However, as the concentration of paraoxon increased the relative proportion of PNP to PNPS and PNPG increased, indicating the capacity of liver to biotransform paraoxon exceeded the capacity to biotransform PNP. Single-pass perfusion in situ of mouse livers with PNP resulted in production of PNPS and PNPG. As with paraoxon, steady-state conditions were achieved in 15-25 min. The extraction ratio of PNP, as well as the metabolic profile, changed markedly with varying concentrations of PNP. At PNP reservoir concentrations of 4 μM or less the extraction ratio of PNP was 1, with all PNP metabolized to PNPS. As PNP concentrations increased (up to 75 μM) both unchanged PNP and PNPG appeared in the effluent. Thus the hepatic biotransformation of PNP was clearly dependent on substrate concentration.