N-Acetylcysteine is a Highly Available Precursor for Cysteine in the Neonatal Piglet Receiving Parenteral Nutrition

Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada T6G 2P5.
Journal of Parenteral and Enteral Nutrition (Impact Factor: 3.15). 03/2006; 30(2):133-42. DOI: 10.1177/0148607106030002133
Source: PubMed


Cysteine (CYS) is accepted as an indispensable amino acid for infants receiving parenteral nutrition (PN), and CYS is unstable in solution. Thus, developing a method to supply CYS in PN for neonates is needed. N-acetyl-L-cysteine (NAC) is stable in solution and safe for use in humans; therefore, NAC may be a means of supplying parenteral CYS.
We determined the bioavailability of NAC in intravenously (IV)-fed piglets randomized to 1 of 4 diet treatments, each supplying 0.3 g/kg/d methionine and either 0.2 g/kg/d CYS (CON), 0 NAC (zeroNAC), 0.13 NAC (lowNAC), or 0.27 g/kg/d NAC (highNAC). Piglets (2 days old; 1.8 kg, n = 20) were surgically implanted with femoral and jugular catheters. On day 3 postsurgery, test diets were initiated and continued until day 8. Piglets were weighed daily. Blood was sampled 6 hours before test diet initiation and at 0, 6, 12, 18, 24, 36, 48, 60, 72, 84, 96, 108, and 120 hours. Urine was collected on ice in 24-hour sample periods.
Total mean weight gain was not different between groups; however, average daily gain in the zeroNAC and lowNAC groups declined significantly (p < .05) over the 5-day treatment period. Nitrogen retention was similar between the CON and highNAC groups, both were higher than the lowNAC group, and the zeroNAC treatment produced the lowest nitrogen retention. NAC percent retention was not different between lowNAC and highNAC and was 85.4% and 82.6%, respectively. Plasma NAC was higher in highNAC than lowNAC (p < .05).
These data demonstrate that NAC is available as a precursor for CYS to support growth and protein (nitrogen) accretion in piglets administered a parenteral solution.

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    • "Cys, which participates in a variety of metabolic pathways involving Met, glutathione, 34 coenzyme A, and taurine (Stipanuk, 2004). Studies suggest Cys should be considered a 35 conditionally indispensable AA (Shoveller et al., 2006) contingent on Met status of the 36 animal. However, dietary supplementation of Cys is complicated because its free 37 sulfhydryl group is capable of spontaneous oxidation, resulting in product instability. "
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    ABSTRACT: Relative bioavailability and toxicity of N-acetyl-l-Cys (NAC) were evaluated in 9-d chick growth assays. The bioavailability of NAC relative to Cys was determined by feeding young chicks a highly purified crystalline AA diet singly deficient in Cys. Bio-availability estimates were obtained using standard slope-ratio methodology. N-Acetyl-l-cysteine was shown to be as effective as Cys in supporting chick growth, and was assigned a relative bioavailability value of 100%. To assess toxicity, a nutritionally adequate corn-soybean meal diet was supplemented with graded concentrations of NAC (isomolar to 10, 20, 30, or 40 g/kg of Cys, as-fed). When NAC supplied 10 or 20 g/kg of Cys, chick growth performance was unaffected, but NAC supplying 30 or 40 g/kg of Cys reduced (P < 0.05) BW gain by 13 and 34%, respectively, relative to the unsupplemented control diet. Only plasma-free NAC was substantially increased (P < 0.05) because of excess dietary NAC; plasma-free Cys was unaltered. We concluded that dietary NAC is efficacious in supplying Cys in support of chick growth, and only large excesses of NAC are growth depressing. Hence, the human clinical benefits of oral NAC likely result from its ability to deliver Cys safely and effectively to the portal circulation.
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    ABSTRACT: Animal studies have shown that several methionine (Met) and cysteine (Cys) analogs or precursors have L-Met- and L-Cys-sparing activity. Relative oral bioavailability (RBV) values, with the L-isomer of Met and Cys set at 100% (isosulfurous basis), are near 100% for D-Met for animals but only about 30% for humans. Both the OH and keto analogs of Met have high RBV-sparing values, as does N-acetyl-L-Met (the D-isomer of acetylated Met has no bioactivity). L-Homocysteine has an RBV value of about 65% for Met sparing in rats and chicks, but D-homocysteine has little if any Met-sparing activity. S-Methyl-L-Met can partially spare Met, but only when fed under dietary conditions of choline/betaine deficiency. Relative to L-Cys, high RBV values exist for L-cystine, N-acetyl-L-Cys, L-homocysteine, L-Met, and glutathione, but D-cystine, the keto analog of Cys, L-cysteic acid, and taurine have no Cys-sparing activity. l-2-Oxothiazolidine-4-carboxylate has an RBV value of 75%, D-homocysteine 70%, and DL-lanthionine 35% as Cys precursors. Under dietary conditions of Cys deficiency and very low inorganic sulfate (SO4) ingestion, dietary SO4 supplementation has been shown to reduce the Cys requirement of several animal species as well as humans. Excessive ingestion of Met, Cys, or cystine has also been studied extensively in experimental animals, and these sulfur amino acids (SAA) are well established as being among the most toxic of all amino acids that have been studied. Even though Cys and its oxidized product (cystine) are equally efficacious at levels at or below their dietary requirements for maximal growth, Cys is far more toxic than cystine when administered orally in the pharmacologic dosing range. Isosulfurous (excess) levels of cystine, N-acetyl-L-Cys, or glutathione are far less growth depressing than L-Cys when 6 to 10 times the minimally required level of these SAA compounds are fed to chicks.
    Preview · Article · Jul 2006 · Journal of Nutrition
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    ABSTRACT: Recent studies using the indicator amino acid oxidation (IAAO) technique in TPN-fed piglets and infants have been instrumental in defining parenteral amino acid requirements. None of the commercial products in use are ideal when assessed against these new data. Our objectives were to determine whether the oxidation of an indicator amino acid would decline with the addition of amino acids that were limiting in the diets of TPN-fed piglets, and to use this technique to identify limiting amino acids in a new amino acid profile. Piglets (n = 26) were randomized to receive TPN with amino acids provided by Vaminolact (VM) or by a new profile (NP). After 5 d of TPN administration, lysine oxidation was measured using a constant infusion of L- [1-(14)C]-lysine. Immediately following the first IAAO study, the piglets were further randomized within diet group to receive either 1) supplemental aromatic amino acids (AAA), 2) sulfur amino acids (SAA) or 3) both (AAA+SAA) (n = 4-5 per treatment group). A second IAAO study was carried out 18 h later. In the first IAAO study, lysine oxidation was high for both groups (18 vs. 21% for VM and NP, respectively, P = 0.055). The addition of AAA to VM induced a 30% decline in lysine oxidation compared with baseline (P < 0.01). Similarly, SAA added to NP lowered lysine oxidation by approximately 30% (P < 0.01). The application of the IAAO technique facilitates rapid evaluation of the amino acids that are limiting to protein synthesis in parenteral solutions.
    Full-text · Article · May 2007 · Journal of Nutrition
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