R,S-1,3-BUTANEDIOL ACETOACETATE ESTERS, POTENTIAL ALTERNATES TO LIPID EMULSIONS FOR TOTAL PARENTERAL-NUTRITION

We present the preparation and characterization of totally and partially water-soluble forms of fat which could replace emulsions of long-chain triacylglycerols for total parenteral nutrition. R,S-1,3-butanediol acetoacetate monoesters and diester represent pH-neutral, sodium-free, diffusible precursors of ketone bodies. The latter are water-soluble forms of fat that are well used by peripheral tissues except in prolonged starvation and diabetic ketoacidosis. The esters are rapidly hydrolyzed by plasma and tissue esterases. R,S-1,3-butanediol liberated is oxidized in liver to R,S-beta-hydroxybutprate. Reducing equivalents generated during this oxidation are trapped in the conversion of acetoacetate to R-beta-hydroxybutyrate. So both the carbon and the hydrogen of the esters are exported from the liver to peripheral tissues in the form of R- + S-beta-hydroxybutyrate. Thus, contrary to what occurs after administration of ethanol or R,S-1,3-butanediol alone, administration of the R,S-1,3-butanediol acetoacetate esters does not lead to major shifts in the liver's [NADH]/[NAD(+)] ratio. Such shifts are responsible for the toxic effects of ethanol on the liver. It is therefore likely that long-term administration of the R,S-1,3-butanediol acetoacetate esters will not lead to liver toxicity.