Original Contribution ANTIOXIDANT ROLE OF N-ACETYL CYSTEINE ISOMERS FOLLOWING HIGH DOSE IRRADIATION RACHEL NEAL,* RICHARD H. MATTHEWS,* †‡ PAULA LUTZ, § and NURAN ERCAL* *Department of Chemistry, University of Missouri at Rolla, Rolla, MO, USA; † Department of Radiation Oncology, PCRMC, Rolla, MO, USA; ‡ Department of Radiation Oncology, Beth Israel-Deaconess Medical Center/Harvard Medical School, Boston, MA, USA; and § Department of Biological Sciences, University of Missouri at Rolla, Rolla, MO, USA (Received 16 July 2002; Revised 22 November 2002; Accepted 3 December 2002) Abstract—High dose, acute radiation exposure, as in radiation accidents, induces three clinical syndromes that reflect consequences of oxidative protein, lipid, and DNA damage to tissues such as intestine, lung, and liver. In the present study, we irradiated C57BL/6 mice with 18 Gy whole-body radiation (XRT) and evaluated N-acetyl cysteine (NAC) isomers LNAC and DNAC as potential radioprotectors under conditions that would model the gastrointestinal syndrome. We focused on tissues thought not immediately involved in the gastrointestinal syndrome. Both LNAC and DNAC protected the lung and red blood cells (RBC) from glutathione (GSH) depletion following radiation exposure. However, only LNAC also supplemented the spleen GSH levels following XRT. Protection from increased malondi- aldehyde (MDA) levels (lung) and increased 8-hydroxy-deoxyguanosine (8-oxo-dG) presence (liver) following XRT was observed with treatment by either isomer of NAC. These results imply that either NAC isomer can act as a radioprotectant against many aspects of oxidative damage; chirality is only important for certain aspects. This pattern would be consistent with direct action of NAC in many radioprotection and repair processes, with a delimited role for NAC in GSH synthesis in some aspects of the problem. © 2003 Elsevier Science Inc. Keywords—Gastrointestinal syndrome, NAC, Stereoisomers, C57Bl/6, Whole-body irradiation, Free radicals INTRODUCTION A prodromal syndrome followed by three acute or sub- acute lethal syndromes have been defined for the situa- tion of whole-body radiation exposure as might occur in a nuclear accident or a nuclear attack. At very high doses, of the order of 100 Gy, death can be expected in 24 – 48 h and appears to result from neurologic and cardiovas- cular breakdown; this is known as the cerebrovascular syndrome. The gastrointestinal syndrome follows about 4 –10 d after exposure to whole-body doses in the range of 5–12 Gy and is associated with bloody diarrhea and breakdown of the gastrointestinal mucosa. The hemato- poietic, or bone marrow syndrome, is induced in the range of 3– 8 Gy and requires several weeks to be ex- pressed as the cells of the immune system are lost. The physiological mechanisms inducing radiation injury have been extensively explored, resulting in increased radia- tion safety in the clinical setting [1– 4]. The medical crisis following the Chernobyl nuclear accident and the threat of terrorist nuclear attack have raised awareness that high dose, total-body irradiation may occur and result in death due to the gastrointes- tinal and hematopoietic syndromes [4,5]. The combi- nation of the prodromal syndrome followed by the gastrointestinal syndrome and bone marrow death in- duces dehydration, anemia, and infection that leads to irreversible shock [6]. Current treatment for the sub- acute gastrointestinal and hematopoietic syndromes includes supportive therapy such as plasma volume expansion, platelets, and antibiotics to prevent dehy- dration and infection and promote bone marrow re- population [7]. Human total-body exposure to a dose above 10 Gy has been regarded as uniformly fatal [4]. There is some thought now that, with therapeutic intervention, survival may be possible at up to 15 Gy of total-body irradiation; but, beyond 20 Gy the symp- toms would not be manageable [8]. Address correspondence to: Dr. Nuran Ercal, University of Missouri at Rolla, Department of Chemistry, 142 Schrenk Hall, Rolla, MO 65409, USA; Tel: (573) 341-6950; Fax: (573) 341-6033; E-Mail: nercal@umr.edu. Free Radical Biology & Medicine, Vol. 34, No. 6, pp. 689 – 695, 2003 Copyright © 2003 Elsevier Science Inc. Printed in the USA. All rights reserved 0891-5849/03/$–see front matter doi:10.1016/S0891-5849(02)01372-2 689