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 of net fluid secretion into the gastrointestinal tract. We have examined the possibility that the mechanism of diquat toxicity in the small intestine involves redox cycling of the bipyridyl leading to a disturbance of biochemical function and oxidative stress. Experiments performed in vitro showed that diquat (10 microM to 1 mM) produced an increase in activity of the pentose phosphate pathway in rat small intestinal tissue slices, suggesting that there was oxidation of NADPH even at concentrations of diquat which do not cause intestinal fluid secretion in anaesthetized rats. When the effect of diquat on pentose phosphate activity was measured in rats in situ at a dose which causes maximal fluid secretion [50 mM diquat dibromide (DQBr2)], production of 14CO2 from [1-14C]-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. Diquat 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 intestine is associated with redox cycling of bipyridyl leading to depletion of NADPH.
Rawlings
J M
JM
Zeneca Central Toxicology Laboratory, Macclesfield, Cheshire, U.K.
Wyatt
I
I
Heylings
J R
JR
D000818:Animals; D002245:Carbon Dioxide / Q000378:metabolism; D004178:Diquat / Q000378:metabolism* / Q000633:toxicity; D005947:Glucose / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism*; D007421:Intestine, Small / Q000378:metabolism*; D008297:Male; D009243:NAD / Q000378:metabolism; D009249:NADP / Q000378:metabolism; D010084:Oxidation-Reduction; D010427:Pentose Phosphate Pathway / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D015219:Substrate Cycling
D009243:NAD; D002245:Carbon Dioxide; D009249:NADP; D004178:Diquat; D005947:Glucose