Effect of glutathione depletion on aminopyrine and formaldehyde metabolism.
In previous studies, diethylmaleate (DEM)- and phorone-induced hepatic glutathione (GSH) depletion in rats was accompanied by impaired evolution of 14CO2 from the N-14C-labeled methyl groups of aminopyrine, which in turn was attributed to impaired generation of formaldehyde, its subsequent oxidation to formate, or to some combination of both. In the present study, l-buthionine sulfoximine (BSO)-induced hepatic GSH depletion was also accompanied by decreased evolution of CO2 from aminopyrine, but the extent of the fall in CO2 was less than that induced by DEM or phorone, even though the decrease in hepatic GSH was comparable with all three GSH-lowering compounds. Incubation of freshly prepared normal hepatic microsomes in vitro with the GSH-lowering agents resulted in impaired aminopyrine-N-demethylase (APDM) activity with inhibition by phorone greater than DEM greater than BSO. By contrast, hepatic microsomes prepared from rats pretreated with these compounds had normal APDM activity. 14CO2 evolution from i.p. administered [14C]formaldehyde was not impaired by any of the GSH-lowering compounds. Thus, assessment of APDM activity and formaldehyde metabolism did not unequivocally establish the mechanism(s) by which CO2 evolution from aminopyrine is depressed by DEM, phorone and BSO, although low GSH is likely to impair metabolism of formaldehyde formed in liver after demethylation of aminopyrine. Quantitative differences in the degree of depression of CO2 evolution suggest that at least DEM and phorone exert an additional inhibitory effect by a GSH-independent mechanism. This may involve inhibition of aminopyrine-N-demethylase activity.
Bhatt
H S
HS
Department of Internal Medicine, University of Texas Health Science Center, Southwestern Medical School, Dallas 75235.
Lober
S B
SB
Combes
B
B
D000632:Aminopyrine / Q000378:metabolism*; D000633:Aminopyrine N-Demethylase / Q000037:antagonists & inhibitors; D000818:Animals; D001944:Breath Tests; D019328:Buthionine Sulfoximine; D005557:Formaldehyde / Q000378:metabolism*; D005561:Formates / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism / Q000502:physiology*; D007659:Ketones / Q000494:pharmacology; D008297:Male; D008298:Maleates / Q000494:pharmacology; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives / Q000494:pharmacology; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains
D005561:Formates; D007659:Ketones; D008298:Maleates; D000632:Aminopyrine; C030544:formic acid; D008717:Methionine Sulfoximine; D005557:Formaldehyde; D019328:Buthionine Sulfoximine; C018637:phorone; D000633:Aminopyrine N-Demethylase; C014476:diethyl maleate; D005978:Glutathione