Pulmonary indoleamine 2,3-dioxygenase activity and its significance in the response of rats, mice, and rabbits to oxidative stress.
The physiological significance of the enzyme indoleamine 2,3,-dioxygenase (IDO) (EC 1.13.11.17), which consumes superoxide anion (O2-), is not known. Since this enzyme is found in high concentrations in lung tissue, we examined the possibility that IDO may protect against chemically induced oxidative stress in the lung. The induction of IDO by bacterial lipopolysaccharide (LPS) was found to be 20-fold in the mouse and 4-fold in the rat, but did not confer protection against paraquat-induced pulmonary toxicity. Moreover, paraquat, when dosed to rats or mice, did not induce pulmonary IDO activity. An elevation in the intracellular O2- concentration was sought by incubating lung slices with 5 mM diethyldithiocarbamate (DDTC) (to inhibit SOD), paraquat (10(-4) M), or methylene blue (10(-4) M) or under an atmosphere of 100% oxygen. These attempts did not enhance the IDO activity in lung slices prepared from control or LPS-treated rats and mice. There was also no evidence that the uptake of an IDO substrate, tryptophan, was limiting for IDO activity in rat and mouse lung slices. We have concluded in the case of rats and mice that the pulmonary IDO activity, even following induction, is too low for O2- to be the rate-limiting factor. For this reason IDO cannot act as a protective enzyme by scavenging O2- in the lung of these species. However, in the rabbit, a species comparatively resistant to paraquat- and oxygen-induced lung damage, pulmonary IDO activity is 170 times that of rats or mice. IDO activity in rabbit lung slices was increased 4-fold by incubation with 5 mM DDTC and 10-fold by incubation with methylene blue (10(-4) M). However, paraquat (10(-4) M and oxygen (100% atmosphere) were able to enhance IDO activity (5-fold) only when SOD had previously been inhibited. We have concluded that in the rabbit lung IDO is able to scavenge O2- and therefore has the potential to act as a protective enzyme in this species.
Daley-Yates
P T
PT
Imperial Chemical Industries, PLC, Central Toxicology Laboratory, Alderley Park, Macclesfield, United Kingdom.
Powell
A P
AP
Smith
L L
LL
D000818:Animals; D049308:Dioxygenases; D004050:Ditiocarb / Q000494:pharmacology; D004790:Enzyme Induction; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000201:enzymology*; D008297:Male; D051379:Mice; D010100:Oxygen / Q000378:metabolism; D010105:Oxygenases / Q000096:biosynthesis / Q000378:metabolism* / Q000502:physiology; D010269:Paraquat / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D013045:Species Specificity; D013482:Superoxide Dismutase / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism
D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D008070:Lipopolysaccharides; D013481:Superoxides; D004050:Ditiocarb; D010105:Oxygenases; D049308:Dioxygenases; D013482:Superoxide Dismutase; D010269:Paraquat; D010100:Oxygen