RELATIONSHIP BETWEEN PARATHION AND PARAOXON TOXICOKINETICS, LUNG METABOLIC-ACTIVITY, AND CHOLINESTERASE INHIBITION IN GUINEA-PIG AND RABBITLUNGS

Kinetic parameters of parathion and paraoxon uptake were determined in isolated and perfused rabbit and guinea pig lungs. They were related to organophosphate-induced lung cholinesterase inhibition. A single pa ss procedure was used to perfuse the lungs with an artificial medium p erfusate containing paraoxon or parathion. The paraoxon and parathion concentrations were determined in the effluents collected at chosen in tervals over an 18-min period beginning at the start of perfusion. Thr ee inflowing concentrations (1 nmol/ml, 10 nmol/ml, and 20 nmol/ml) we re tested in guinea pig lungs and one (10 nmol/ml) in rabbit lungs. Ch olinesterase activity was determined at time 0 and at the end of the e xperiment. The lungs abundantly extracted paraoxon and parathion over the perfusion period. The extraction ratio was consistently greater in guinea pig than in rabbit lungs. The uptake velocity varied biexponen tially in time, suggesting the existence of two compartments. Initial uptake velocities (A, B) and slopes (alpha and beta) were calculated f or both compartments. In guinea pigs, A, B and A + B increased proport ionally to the supply rate of paraoxon and parathion while a and b rem ained constant. No significant difference was observed between parathi on and paraoxon uptake kinetics. Parameter B was the only one to diffe r significantly between the two species (rabbits: 8.19 +/- 1.53 for pa rathion and 6.85 +/- 1.26 for paraoxon; guinea pigs: 12.75 +/- 0.88 fo r parathion and 15.02 +/- 3.84 for paraoxon). In the lungs of both spe cies, there was a linear relation between y, the percentage of choline sterase inhibition induced by either organophosphate, and X, the total amount of drug taken up by the lung tissue (in nmol/g/18 min). The fo llowing equations were obtained: y = 0.128 x + 0.979 (R(2) = 0.89, p < 0.001 for paraoxon); y = 0.120 x - 6.57 (R(2) = 0.82, p < 0.005 for p arathion). No difference was observed between the two organophosphates . After treatment with the cytochrome P450 inhibitor piperonyl butoxid e, the above relations ceased to apply, but this treatment did not inf luence the kinetics of paraoxon and parathion uptake. The IC50 value c alculated for paraoxon, i.e., the paraoxon concentration required to p roduce 50% inhibition of lung cholinesterase activity, was similar for guinea pigs (2.22 10(-7) +/- 0.22 M) and rabbits (2.36 10(-7) +/- 0.2 4 M). In conclusion, the biexponential evolution of the velocity of pa raoxon and parathion uptake by the lungs thus demonstrates the presenc e of two pools. The lower extraction ratios calculated for rabbit lung s reflect the lower initial uptake velocity of the second compartment. In the range of concentrations investigated in guinea pigs, no satura ble mechanism could be demonstrated for paraoxon and parathion. Cytoch rome P450-related lung metabolic activity, through which parathion is converted to paraoxon, appears as a major step in parathion-induced lu ng cholinesterase inhibition, although it does not appear to affect pa rathion toxicokinetics. (C) 1996 Academic Press, Inc.