Effects of the phenacetin metabolite 4-nitrosophenetol on glycolysis and pentose phosphate pathway in human red cells.
Human erythrocytes exposed to 4-nitrosophenetol showed marked alterations of their endogenous metabolism. Rapid ferrihemoglobin formation mediated by the NADPH-dependent enzymic cycling of the nitrosoarene ("Kiese cycle") and extensive GSSG production caused an immediate drain of G-6-P into the pentose phosphate pathway at maximal flow. Despite a 2.4-fold increase in glucose phosphorylation rate and a branching ratio of 97:3 between pentose phosphate pathway and Embden-Meyerhof pathway, the G-6-P supply was obviously insufficient to meet the immense NADPH demand. Thus, a significant recycling of pentose phosphate pathway-derived F-6-P was observed in the order of 65%. Comparison of NADPH regeneration and ferrihemoglobin formation indicates the "Kiese cycle" to be a minor mechanism in ferrihemoglobin production in the case of high 4-nitrosophenetol concentrations. Most probably, reactive intermediates of 4-nitrosophenetol other than N-hydroxy-4-phenetidine, i.e. bicyclic arylamines and glutathione S-conjugates are formed which produce ferrihemoglobin without involvement of NADPH. The experiments have shown that red cells are remarkable robust to tackle the massive oxidative stress as elicited by 4-nitrosophenetol. The immediate metabolic response of the pentose phosphate pathway allows rapid regeneration of reduced glutathione. Thereby, SH-containing enzymes are effectively protected and/or regenerated and hemolysis is kept minimal. Hence, red cells are favourably suited for clearing the blood from N-oxygenated arylamines before they can reach more sensitive target organs.
Gallemann
D
D
Walther-Straub-Institut für Pharmakologie und Toxikologie, Ludwig-Maximilians-Universität München.
Eyer
P
P
D000255:Adenosine Triphosphate / Q000097:blood; D002245:Carbon Dioxide / Q000097:blood; D004912:Erythrocytes / Q000187:drug effects* / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects*; D006593:Hexokinase / Q000097:blood; D006801:Humans; D008706:Methemoglobin / Q000096:biosynthesis; D009243:NAD / Q000097:blood; D009249:NADP / Q000097:blood; D010427:Pentose Phosphate Pathway / Q000187:drug effects*; D010615:Phenacetin / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology
D009243:NAD; D002245:Carbon Dioxide; C037221:4-nitrosophenetole; D009249:NADP; D000255:Adenosine Triphosphate; D008706:Methemoglobin; D006593:Hexokinase; D010615:Phenacetin