The Effect of Glutathione Depletion on 14Co2 Evolution From [14C] Methyl–Labeled Aminopyrine in Intact Rats

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Abstract
The effect of hepatic glutathione depletion on 14CO2 evolution from [14C]methyl–labeled aminopyrine was assessed in fed male Sprague–Dawley rats. Within 30 min of i.p. administration of either diethylmaleate or phorone, hepatic glutathione fell approximately 75 to 80% and remained depressed for the ensuing 120 min. [14C]Aminopyrine was i.p. administered 30 min after the glutathione–lowering agents (zero time) and exhaled 14CO2 was collected at 15–min intervals for the next 120 min. Parameters of 14CO2 exhalation including peak exhalation rate, cumulative exhalation from 0 to 120 min and the elimination rate constant were all impaired in glutathionedepleted rats. Metabolism of the [14C]methyl groups involves N–demethylation with formation of formaldehyde, oxidation to formate and conversion to 14CO2. Glutathione depletion did not affect CO2 evolution from i.p. administered formate or bicarbonate. The glutathione–dependent step presumably involves either or both generation of formaldehyde or its subsequent oxidation to formate.