metabolism and cytotoxic mechanisms of nitroglycerin in isolated rat hepatocytes
نویسندگان
چکیده
it has been proposed that organic nitrates such as glyceryl trinitrate (gtn), used in the treatment of cardiovascular diseases, act by producing nitric oxide (no). however, the biochemical pathway for no formation from gtn is not well understood. in the present study, we showed that nitrate formation from gtn, by isolated rat hepatocytes, was inhibited about 50% when cellular glutathione was depleted and about 40% when cytochrome p-450 was inactivated by skf525a. this suggests that gtn is metabolized and/or no is formed by three pathways in rat hepatocytes: 1) denitrification of gtn by gsh/gsh transferase system; 2) reduction of gtn by reduced cytochrome p-450; and 3) gtn can directly react with protein thiol groups of cellular macromolecules (transnitrosation). at much higher concentrations, gtn was toxic towards hepatocytes (lc 50= 2 mm for 2 h of incubation) and cytotoxicity was accompanied by gsh and atp depletion. depleting gsh and/or inactivating cytochrome p-450 beforehand markedly increased gtn cytotoxicity. the permeable thiol reductant dithioteritol unlike antioxidants was found to be an effective antidote, even if added to the cells an hour after gtn. the results suggest that gtn-induced cytotoxicity is mediated by transnitrosyllation of mitochondrial, structural and vital protein thiols.
منابع مشابه
Metabolism and Cytotoxic Mechanisms of Nitroglycerin in Isolated Rat Hepatocytes
It has been proposed that organic nitrates such as glyceryl trinitrate (GTN), used in the treatment of cardiovascular diseases, act by producing nitric oxide (NO). However, the biochemical pathway for NO formation from GTN is not well understood. In the present study, we showed that nitrate formation from GTN, by isolated rat hepatocytes, was inhibited about 50% when cellular glutathione w...
متن کاملFORMATION AND METABOLISM OF SUGAR METABOLITES, GLYOXAL AND METHYLGLYOXAL, AND THEIR MOLECULAR CYTOTOXIC MECHANISMS IN ISOLATED RAT HEPATOCYTES By
....................................................................................................................... ii ACKNOWLEDGMENTS ................................................................................................. iii TABLE OF CONTENTS................................................................................................... iv LIST OF PUBLICATION AND ABSTRACTS .....
متن کاملThreonine metabolism in isolated rat hepatocytes.
The removal of the 1-carbon of threonine can occur via threonine dehydrogenase or threonine aldolase, this carbon ending up in glycine to be liberated by the mitochondrial glycine cleavage system and producing CO(2). Alternatively, in the threonine dehydratase pathway, the 1-carbon ends up in alpha-ketobutyrate, which is oxidized in the mitochondria to CO(2). Rat hepatocytes, incubated in Krebs...
متن کاملTransport and metabolism of thiamin in isolated rat hepatocytes.
This study examines thiamin transport in isolated rat hepatocytes and its relationship to thiamin phosphorylation. In an Na+ medium, [35S]thiamin, 3 microM, was accumulated rapidly by the cells, and a near study state intra-/extracellular distribution ratio of 3 was attained in 1 min. However, the uptake of radioactivity continued to increase with time owing principally to the accumulation of [...
متن کاملمنابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
عنوان ژورنال:
iranian journal of pharmaceutical sciencesجلد ۸، شماره ۲، صفحات ۱۰۵-۱۱۳
میزبانی شده توسط پلتفرم ابری doprax.com
copyright © 2015-2023