GSH-independent denitration of the nitrate ester of a dihydropyridine derivative in rabbit hepatic cytosol.
The denitration of a dihydropyridine derivative having two nitrate ester groups, 2-nitroxypropyl 3-nitrooxypropyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3, 5-pyridinedicarboxylate (NND), by rabbit hepatic cytosol was investigated. Sephadex G-150 chromatography of ammonium sulfate precipitate (30-60%) from the cytosol demonstrated the presence of two distinct activities (peak I and peak II) responsible for denitration of [14C]-NND. The first peak, peak I, was observed in the presence of dithiothreitol (DTT), but not in the presence of glutathione (GSH). Moreover, the denitration activity of peak I was not inhibited by S-hexyl GSH, an inhibitor of GSH S-transferase (GST), indicating that peak I possessed no GST activity. In contrast, the denitration activity of peak II, having GST activity, required GSH and was inhibited by S-hexyl GSH. These results strongly suggest that the GSH-independent enzyme system(s), in addition to GST, is responsible for denitration of nitrate esters of NND.
Research Center, Taisho Pharmaceutical Co., Ltd., Saitama, Japan.
N
N
Ogawa
T
T
Hirose
K
K
Fukushima
T
T
Suwa
T
T
Satoh
D000818:Animals; D005591:Chemical Fractionation; D003600:Cytosol / Q000378:metabolism; D004095:Dihydropyridines / Q000378:metabolism*; D004229:Dithiothreitol; D005978:Glutathione / Q000378:metabolism*; D005982:Glutathione Transferase / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D009566:Nitrates / Q000378:metabolism*; D005996:Nitroglycerin / Q000378:metabolism; D011817:Rabbits
D004095:Dihydropyridines; D009566:Nitrates; D005982:Glutathione Transferase; D005996:Nitroglycerin; D005978:Glutathione; D004229:Dithiothreitol