Reduction of hepatic tetrahydrofolate and inhibition of exhalation of 14CO2 formed from [dimethylamino-14C]aminopyrine in nitrous oxide-treated rats.
The exhalation of 14CO2 after 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 modify 14C-aminopyrine metabolism to 14CO2 in 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 of 14C-aminopyrine (40 or 400 mumoles per kg) produced a 60% reduction in the peak rate of 14CO2 exhalation and a 45% decrease in the total 14CO2 exhaled within 2 hr. In control experiments, exposure of rats to nitrogen/O2 (1:1) produced no effect on 14C-aminopyrine metabolism to 14CO2. Administration of methionine (1.3 mmoles per kg) 30 min prior to 14C-aminopyrine administration reversed the inhibition of 14CO2 exhalation and reduction in hepatic tetrahydrofolate observed in N2O-exposed animals. Aminopyrine (400 mumoles 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.(ABSTRACT TRUNCATED AT 250 WORDS)
D000632:Aminopyrine / Q000378:metabolism*; D000818:Animals; D001944:Breath Tests; D002245:Carbon Dioxide / Q000502:physiology*; D002250:Carbon Radioisotopes; D005561:Formates / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D006899:Mixed Function Oxygenases / Q000378:metabolism; D009609:Nitrous Oxide / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013763:Tetrahydrofolates / Q000378:metabolism*; D013997:Time Factors
D002250:Carbon Radioisotopes; D005561:Formates; D013763:Tetrahydrofolates; D000632:Aminopyrine; D002245:Carbon Dioxide; D006899:Mixed Function Oxygenases; D009609:Nitrous Oxide