Physiologic, Metabolic, and Toxicologic Profile of 1,3-Butanediol

Ketone bodies are essential energy substrates in the absence of exogenous nutrients, and more recently, they have been suggested to prevent disease and improve longevity. β-hydroxybutyrate (βHB) is the most abundant ketone body. The secondary alcohol, 1,3-butanediol (1,3-BD), is commonly administered to raise βHB bioavailability in vivo and in the absence of nutrient deprivation. However, the concentration of 1,3-BD that yields a systemic concentration of βHB similar to that observed after a 24-hour fast has yet to be determined. To evaluate this knowledge gap, we administered 5%, 10%, or 20% 1,3-BD via the drinking water to adult, male Wistar-Kyoto rats for four weeks. In addition to systemic and excreted βHB concentration, physiologic, metabolic, and toxicologic parameters were measured. We report that only 20% 1,3-BD significantly elevates the systemic and urinary concentrations of βHB. Rats treated with 20% 1,3-BD had a rapid and sustained reduction in body mass. All concentrations of 1,3-BD decreased food consumption, but only the 20% concentration decreased fluid consumption. Urine volume, red blood cell count, and hematocrit suggested dehydration in the 10% and 20% 1,3-BD-treated rats. Finally, 20% 1,3-BD-treated rats presented with indicators of metabolic acidosis and sinusoidal dilation, but no evidence of fatty liver or hepatotoxicity. In summary, we report that 20% 1,3-BD, but not 5% or 10%, produces a systemic concentration of βHB similar to that observed after a 24-hour fast. However, this concentration is associated with deleterious side effects such as body mass loss, dehydration, metabolic acidosis, and sinusoidal dilation. SIGNIFICANCE STATEMENT: 1,3-Butanediol (1,3-BD) is often administered to stimulate the biosynthesis of the most abundant ketone body, β-hydroxybutyrate (βHB), and its purported salubrious effects. This article reports that suprapharmacological concentrations of 1,3-BD are necessary to yield a systemic concentration of βHB similar to that observed after a 24-hour fast, and this is associated with undesirable side effects. On the other hand, low concentrations of 1,3-BD were better tolerated and may improve health independent of its conversion into βHB.