Paraquat inhibits mixed-function oxidation by rat lung

T. K. Aldrich, A. B. Fisher, H. J. Forman

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1089-1093
Number of pages5
JournalJournal of Applied Physiology Respiratory Environmental and Exercise Physiology
Volume54
Issue number4
DOIs
StatePublished - 1983

ASJC Scopus subject areas

  • Physiology
  • Endocrinology

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