Nitroglycerin metabolism in subcellular fractions of rabbit liver. Dose dependency of glyceryl dinitrate formation and possible involvement of multiple isozymes of glutathione S-transferases.
The hepatic transformation of glyceryl trinitrate (GTN), commonly known as nitroglycerin, was studied in subcellular fractions prepared from rabbit livers. Both the cytosolic and microsomal fractions show activity toward GTN metabolism. Moreover, the formation of glyceryl dinitrates (GDNs) seems to be governed by different enzymatic processes in the two fractions. 1,2-GDN was preferentially formed in cytosolic fractions, whereas in microsomal fractions, 1,3-GDN was the predominant product. In cytosolic fractions, increasing starting concentrations of GTN led to a decrease in both the GTN degradation rate and the GDN ratio (1,2-GDN/1,3-GDN), which was mainly accounted for by saturation of the 1,2-GDN formation pathway. Various glutathione S-transferase (GST) inhibitors affected the rate of GDN formation differentially. In cytosolic fractions, 1-chloro-2,4-dinitrobenzene and iodomethane caused no change in the GDN ratio, while sulfobromophthalein, ethacrynic acid, and p-nitrobenzyl chloride decreased the GDN ratio, suggesting that different GST isozymes are inhibited by these agents. In microsomal fractions, no dose-dependent GTN metabolism and related change in the GDN ratios could be observed. With the exception of ethacrynic acid, addition of GST inhibitors did not decrease GDN metabolite production, and even in this case, no change in the GDN ratio was observed. The results suggest that different GTN metabolic pathways are present in the liver, most likely involving different GST isozymes.
Lau
D T
DT
Department of Pharmacy, School of Pharmacy, University of California, San Francisco 94143-0446.
Benet
L Z
LZ
D000818:Animals; D005982:Glutathione Transferase / Q000032:analysis / Q000378:metabolism*; D066298:In Vitro Techniques; D007527:Isoenzymes; D008099:Liver / Q000378:metabolism*; D008297:Male; D005996:Nitroglycerin / Q000031:analogs & derivatives* / Q000378:metabolism*; D011817:Rabbits; D013347:Subcellular Fractions / Q000378:metabolism*
D007527:Isoenzymes; C014509:dinitroglycerol; D005982:Glutathione Transferase; D005996:Nitroglycerin