Reduction of Hepatic Tetrahydrofolate and Inhibition of Exhalation of 14CO2 Formed from [Dimethylamino-14C]Aminopyrine in Nitrous Oxide-Treated Rats

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Abstract
The exhalation of14CO2after the administration of [dimethylamino-14C]aminopyrine to an organism is assumed to reflect the demethylation of aminopyrine by hepatic mixed-function oxidase activity. The formaldehyde formed as a result of the demethylation of aminopyrine is then sequentially oxidized to formic acid and CO2. The last step in the pathway, i.e., formate oxidation, is dependent upon tetrahydrofolate; thus, factors which alter hepatic tetrahydrofolate potentially may modify14C-aminopyrine metabolism to14CO2in vivo.Exposure of rats to nitrous oxide (N2O) produces a significant reduction in hepatic tetrahydrofolate as a result of the inhibition of 5-methyltetrahydrofolate:homocysteine methyltransferase activity (E.C. 2.1.1.13). In the present study, exposure of rats to N2O/O2(1:1) for 4 hr prior to the administration of14C-aminopyrine (40 or 400 Mmoles per kg) produced a 60% reduction in the peak rate of14CO2exhalation and a 45% decrease in the total14CO2exhaled within 2 hr. In control experiments, exposure of rats to nitrogen/O2(1:1) produced no effect on14C-aminopyrine metabolism to14CO2. Administration of methionine (1.3 mmoles per kg) 30 min prior to14C-aminopyrine administration reversed the inhibition of14CO2exhalation and reduction in hepatic tetrahydrofolate observed in N2O-exposed animals. Aminopyrine (400 pmoles per kg) administration to air-breathing rats did not affect the level of urinary formate, but exposure to N2O produced a 40-fold increase. Aminopyrine administration to N2O-exposed rats produced a 75% increase in urinary formate as compared to rats treated with N2O alone. The first-order rate constant for aminopyrine elimination from the plasma, apparent volume of distribution, apparent plasma clearance and the level of hepatic cytochrome P-450 were not affected by N2O exposure. N2O exposure inhibited14CO2exhalation after [N-methyl-14C]morphine administration to a similar degree as that observed after aminopyrine administration. These results indicate that factors which alter the level of hepatic tetrahydrofolate, e.g., nutritional status, N20 exposure or certain drugs, may modify the metabolism of14C-amino-pyrine to14CO2in vivowithout affecting the demethylation of aminopyrine. Thus, such factors must be controlled when the exhalation of14CO2after14C-aminopyrine administration to an organism is used as anin vivomeasure of hepatic drug metabolism.