A series of experiments are described designed to define the basis for the previously reported X-linked polymorphic sensitivity of human spontaneous natural killer activity to gamma and ultraviolet (UV) radiation. Using highly enriched human NK cells we will test the hypotheses that the polymorphic sensitivity of the NK cell to radiation reflects (1) polymorphism in the sensitivity to one or more reactive oxygen intermediates; (2) polymorphic sensitivity to the activation of adenosine disphosphorribosyl polymerase (ADPRP) caused by radiation induced damage to DNA: (3) interaction between these two processes. Family and population studies will be used to test for a correlation between sensitivity to UV and gamma radiation so that the ability to vary wave length can be exploited. Inhibitors of ADPRP will be used in conjunction with radiation and drugs which damage DNA and activate ADPRP to evaluate the role of ADPRP products in inhibition of NK activity and polymorphism in such inhibition. Levels of cellular nicotinamide adenine dinucleotide (NAD), the substrate of ADPRP and levels of ADPRP activity will be determined in radiation resistant and sensitive NK cells prior to and after radiation to determine if the polymorphism lies in the extent of activation or activity of ADPRP. The role or radiation induced reactive oxygen intermediates in the polymorphic sensitivity of NK cells to radiation will be determined by testing for an oxygen effect, and by the use of exogenous generating and scavenging systems for reactive oxygen intermediates, including radiosensitizing and radioprotective drugs. If evidence of a role for each intermediate is obtained, then critical enzymes of scavenging oxygen intermediates, including glutathione oxidase, glutathione reductase and glucose-6-phophatase dehydrogenase will be assayed in resistant and sensitive cells, prior to and after radiation. Determination of the gamma radiation dose and UV wave length dependence of alterations in any of these enzymes and the sensitivity of any enzyme alterations to activation and inhibition of ADPRP will allow determination of how the two major effects of radiation--generation of reactive oxygen intermediates and DNA strand breakage activation of ADPRP interact to result in polymorphic sensitivity of NK activity to radiation.
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