BASIC NUTRITIONAL INVESTIGATION Effects of Parenteral Nutrition Supplemented With Glutamine or Glutamine Dipeptides on Liver Antioxidant and Detoxication Systems in Rats Bele ´n Matilla, MD, Juan Ortı ´z, MD, Paquita Gonza ´lez, PhD, Fructuoso Garcı ´a-Dı ´ez, MD, PhD, Francisco Jorquera, MD, PhD, Jesu ´s M. Culebras, MD, PhD, Javier Gonza ´lez-Gallego, MD, PhD, and Marı ´a J. Tun ˜o ´n, PhD From the Hospital of Leo ´n; and the Department of Physiology, University of Leo ´n, Leo ´n, Spain Our aim was to determine the effects of glutamine or alanyl glutamine parenteral supplementation on the liver oxidant/antioxidant balance and on cytochrome-P450-mediated detoxication in rats. Animals were infused for 5 d with standard total parenteral nutrition (TPN), glutamine-enriched TPN, or alanyl glutamine-enriched TPN. The hepatic concentration of glutathione was reduced, and the levels of thiobarbituric-acid-reactive substances (TBARS) were increased in animals receiving standard TPN. Both glutamine and alanyl glutamine supplementation normalized glutathione, but thiobarbituric-acid-reactive substance concentration was only decreased by alanyl glutamine. This effect was parallel to a partial recovery of the activity of antioxidant enzymes. Cytochrome-P450 liver content, cytochrome-P450- dependent monooxygenases, and antipyrine clearance were not modified by glutamine or alanyl glu- tamine. Our data suggest a better protection against free radicals by alanyl glutamine supplementation and an absence of effects of both glutamine and alanyl glutamine on liver oxidative metabolism. Nutrition 2000;16:125–128. ©Elsevier Science Inc. 2000 Key words: parenteral nutrition, glutamine, alanyl glutamine, antioxidant and detoxication systems, rats INTRODUCTION Glutamine is an amide amino acid, usually considered non- essential because it can be synthetized from glutamic acid and ammonia. Glutamine plays a role in multiple metabolic functions by acting not only as a precursor for protein synthesis but also as an important intermediary in a large number of metabolic pathways. It has been shown in both experimental and clinical settings that in all situations with hypercatabolism (prolonged starvation, surgery, burns, major injury) there is an intracellular deficiency of glutamine with an accelerated muscle and lung glutamine efflux and damage to the gut epithelium. Supplementation with glutamine improves nitrogen balance, enhances the rate of protein synthesis, and preserves the integrity of the mucosa. 1 If maintenance of intracellular glutamine pools promotes conservation of muscle protein and improves the regulation of amino acid homeostasis, glutamine supplementation could be considered in the framework of clinical nutrition. 2 Critical illness is associated with a depletion of the liver, muscle, and plasma glutathione stores, resulting in reduced anti- oxidant capacity and oxidative damage. 3 Glutamine is an efficient precursor of glutathione and may contribute through changes in glutathione levels to protect hepatic function. In addition, because protein body reserve and diet amino-acid levels have a major role in liver detoxication systems, 4,5 it is worthwhile to explore the effects of glutamine supplementation on liver-oxidative metabo- lism and on the activities of the cytochrome-P450-dependent monooxygenases. The purpose of our study was to investigate the effects of glutamine parenteral supplementation on the liver oxidant/ antioxidant balance and on cytochrome-P450-mediated detoxica- tion in rats. Because of the limitations that hamper the use of glutamine in routine clinical settings, 1 both glutamine and alanyl glutamine parenteral formulations were used. MATERIALS AND METHODS Animals and Experimental Procedures Male Wistar rats (42 animals; Charles River, Barcelona, Spain) weighing between 220 and 260 g were fed standard rat chow (Purina Chow A03, Panlab Ltd, Barcelona, Spain) with free access to tap water and kept in temperature- and humidity-controlled animal quarters under a 12-h light-and-dark cycle. All the exper- iments were performed according to European 6 and Spanish 7 reg- ulations concerning animal experimentation, and we followed the recommendations in the Guide for Care and Use of Laboratory Animals. 8 Animals were anesthetized with sodium pentobarbital (45 mg/kg intraperitoneally). The right internal jugular vein was cath- eterized with Silastic tubing (PE-50, Dow Corning Corp., Midland, MI, USA). The catheters were exteriorized in the scapular region and secured to the deep fascia with a stainless-steel button. After the catheter was threaded through a flexible wire sheath, the combined unit was attached to a swivel apparatus that allowed the animals to move freely. The animals were randomly assigned to one of the following groups (n = 8 –12 animals/group): a) chow ad libitum and intra- venous saline (control), b) standard total parenteral nutrition (TPN) group, c) glutamine-enriched TPN, and d) alanyl glutamine- enriched TPN. The animals receiving intravenous parenteral nu- Correspondence to: Marı ´a J. Tun ˜o ´n, PhD, Departamento de Fisiologı ´a, Universidad de Leo ´n, Campus Universitario, 24071 Leo ´n, Spain. E-mail: dfimtg@unileon.es Nutrition 16:125–128, 2000 0899-9007/00/$20.00 ©Elsevier Science Inc., 2000. Printed in the United States. All rights reserved. PII S0899-9007(99)00265-8