TY - JOUR
T1 - Paraquat inhibits mixed-function oxidation by rat lung
AU - Aldrich, T. K.
AU - Fisher, A. B.
AU - Forman, H. J.
PY - 1983
Y1 - 1983
N2 - The effect of paraquat on 7-ethoxycoumarin (7-EC) deethylation, an NADPH-dependent cytochrome P-450-linked reaction, was studied in isolated rat lungs. Control lungs oxidatively deethylated 7-EC at a constant rate, metabolizing 178 ± 12 nmol/g dry wt in 50 min (n = 3, mean ± SE). When glucose was omitted from the perfusate, 7-EC deethylation was lower (85 ± 17 nmol/g, P < 0.05), and the rate progressively decreased, suggesting inadequate pentose shunt regeneration of NADPH. During perfusion with paraquat (10-3 M), 7-EC metabolism was still lower (75 ± 5 nmol/g in the presence of glucose and 18 ± 4 nmol/g in the absence of glucose, P < 0.05). Addition of lactate plus pyruvate partially restored 7-EC deethylase activity in control lungs but had no effect in lungs perfused with paraquat. Varying perfusate paraquat concentrations (10-6 to 10-3 M) inhibited 7-EC deethylation in a dose-dependent fashion (r = 0.79, P < 0.02). Oxidative demethylation of p-nitroanisole, another cytochrome P-450-linked reaction, was similarly inhibited by paraquat. In contrast, microsomes isolated from paraquat-perfused lungs showed no inhibition of 7-EC metabolism (measured in the presence of an NADPH-regenerating system). We conclude that paraquat depleted NADPH in the isolated lung to a sufficient extent to impair mixed-function oxidation. Such NADPH depletion may play a role in the toxicity of paraquat.
AB - The effect of paraquat on 7-ethoxycoumarin (7-EC) deethylation, an NADPH-dependent cytochrome P-450-linked reaction, was studied in isolated rat lungs. Control lungs oxidatively deethylated 7-EC at a constant rate, metabolizing 178 ± 12 nmol/g dry wt in 50 min (n = 3, mean ± SE). When glucose was omitted from the perfusate, 7-EC deethylation was lower (85 ± 17 nmol/g, P < 0.05), and the rate progressively decreased, suggesting inadequate pentose shunt regeneration of NADPH. During perfusion with paraquat (10-3 M), 7-EC metabolism was still lower (75 ± 5 nmol/g in the presence of glucose and 18 ± 4 nmol/g in the absence of glucose, P < 0.05). Addition of lactate plus pyruvate partially restored 7-EC deethylase activity in control lungs but had no effect in lungs perfused with paraquat. Varying perfusate paraquat concentrations (10-6 to 10-3 M) inhibited 7-EC deethylation in a dose-dependent fashion (r = 0.79, P < 0.02). Oxidative demethylation of p-nitroanisole, another cytochrome P-450-linked reaction, was similarly inhibited by paraquat. In contrast, microsomes isolated from paraquat-perfused lungs showed no inhibition of 7-EC metabolism (measured in the presence of an NADPH-regenerating system). We conclude that paraquat depleted NADPH in the isolated lung to a sufficient extent to impair mixed-function oxidation. Such NADPH depletion may play a role in the toxicity of paraquat.
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U2 - 10.1152/jappl.1983.54.4.1089
DO - 10.1152/jappl.1983.54.4.1089
M3 - Article
C2 - 6853285
AN - SCOPUS:0020632225
SN - 0161-7567
VL - 54
SP - 1089
EP - 1093
JO - Journal of Applied Physiology Respiratory Environmental and Exercise Physiology
JF - Journal of Applied Physiology Respiratory Environmental and Exercise Physiology
IS - 4
ER -