N-Acetyl-L-Tyrosine (N-Acetyl-Tyrosine, N-acetyltyrosine, NAT) is a novel aromatic amino acid derivative commonly found in pre-workout drinks or other ergogenic sports supplements. This compound is purported to increase the bioavailability of L-Tyrosine. It may also be formed intrahepatically by the enzyme N-acetyltransferase as a mechanism of disposing aromatic amino acids (L-Phenylalanine, L-Tyrosine, L-Dopa).
N-Acetyl-Tyrosine has a water solubility of 2.3 mg/ml, whereas L-Tyrosine has a water solubility of 0.49 mg/ml. Increasing a compounds water solubility is a method that may enhance bioavailability, especially if the compound is particularly insoluble. Conversely, increasing water solubility may actually negatively impact its kinetics by shortening its half-life through urinary excretion. In the case of L-tyrosine, although it has limited water solubility, it has been shown to have adequate bioavailability. In humans, doses as low as 100 mg have been shown to elevate plasma tyrosine levels for as long as 7 hours (1). Doses as high as 7 grams have produced plasma tyrosine levels 223% above baseline (2). As we will see in the next section, doses of N-Acetyl-Tyrosine as high as 5 grams have only shown an elevation of tyrosine of 25% from baseline.
Since NAT does not possess intrinsic pharmacological properties, the most important question is: Does this compound actually become L-tyrosine? The answer is yes, albeit inefficiently. The enzymes Aminoacylase I-III are primarily located in the kidneys and are responsible for removing the acetyl group from the tyrosine molecule (3). In 1985, a proof-of-concept rodent study was designed to determine the utility of replacing the much less soluble tyrosine, with the much more soluble NAT, for total parenteral nutrition (4). They found that, at a dose of 0.5 mmol/kg body weight, NAT infusion was "not sufficient to increase plasma tyrosine concentrations above fasting levels." Converting this dose to a Human Equivalent Dose (HED) times Body Surface Area (BSA) equals a dose of about 1.25 grams. Furthermore, the study also confirmed the inefficiency of N-acetyl removal by measuring the amount of unchanged compound in the urine. With radioactive carbon tracing, they found that 74% of the supplemented form was lost in the urine as unchanged NAT, and only 23% was lost as tyrosine. This amounts to a very inefficient intrarenal conversion rate of about 25%.
Two years later, the study was repeated in humans, although using much higher levels of NAT (5). In this study they compared the usefulness of N-Acetyl-Tyrosine as a more soluble amino acid precursor by infusing these compounds as an IV bolus (5 grams), or as a 4 hour IV infusion. Similar to the rodent study, they found that the NAT infusion only yielded meager increases in plasma tyrosine (up to 25% from baseline), and that the majority (56%) of NAT was excreted unchanged into the urine. The authors commented: "We conclude that under these conditions the usefulness of NAT ... as precursors for the corresponding amino acids in humans is not apparent."
Blood Brain Barrier (BBB)
One of the most discussed uses for N-Acetyl-Tyrosine on the internet concerns the elevation brain tyrosine levels. The idea is that NAT, being a precursor to L-Tyrosine, would allow for greater BBB penetration as a function of direct penetration, or by increasing plasma tyrosine pools through stepwise conversion into L-tyrosine via N-deacetylation, and therefore could be useful in increasing mood, or as a general nootropic. Unfortunately, as the former sections discuss, NAT is a very inefficient tyrosine pro-drug. With regards to the former, a 1989 study analyzed the ability of 3 different compounds in elevating central tyrosine levels when compared to tyrosine itself (6). Both O-phospho-L-tyrosine and L-tyrosine methyl ester were successfully bioequivalent to tyrosine, whereas N-Acetyl-Tyrosine was ineffective.
- Inefficient pro-drug to L-tyrosine
- The majority of N-Acetyl-L-Tyrosine is excreted as unchanged compound
- Doses as high as 5 grams in humans have only produced meager elevations in plasma tyrosine
- No BBB penetration
- Much greater water solubility; unknown significance