EVIDENCE FOR REDOX CYCLING OF DIQUAT IN RAT SMALL-INTESTINE

It has previously been established that acute diquat (1,1'-ethylene, 2 ,2'-bipyridilium) toxicity in the rat is associated with stimulation o f net fluid secretion into the gastrointestinal tract. We have examine d the possibility that the mechanism of diquat toxicity in the small i ntestine involves redox cycling of the bipyridyl leading to a disturba nce of biochemical function and oxidative stress. Experiments performe d in vitro showed that diquat (10 mu M to 1 mM) produced an increase i n activity of the pentose phosphate pathway in rat small intestinal ti ssue slices, suggesting that there was oxidation of NADPH even at conc entrations of diquat which do not cause intestinal fluid secretion in anaesthetized rats. When the effect of diquat on pentose phosphate act ivity was measured in rats in situ at a dose which causes maximal flui d secretion [50 mM diquat dibromide (DQBr(2))], production of (CO2)-C- 14 from [1-C-14]-glucose increased by 278 +/- 28% (N = 4) within 1 hr of exposure to diquat. Under these same conditions, the tissue content of NADPH in the proximal small intestine was significantly depleted, though there was no corresponding increase in NADP(+) concentration. D iquat had no effect on tissue concentrations of either the reduced or oxidized forms of NAD. It is likely that NADPH oxidation at low diquat concentrations can be adequately compensated for by mechanisms within the tissue which protect against oxidative stress. However, the data also suggest that diquat-induced fluid secretion in the rat small inte stine is associated with redox cycling of bipyridyl leading to depleti on of NADPH.