Metabolism in vivo of 1, 3-butanediol in the rat

Abstract

The metabolism of 1, 3-butanediol (BD) was investigated in vitamin B 12 -deficient and normal rats and in liver slice and diaphragm systems. Body weight gain and feed efficiency were determined in rats fed ad libitum for five weeks on a basal 5% BD or 5% sodium propionate diet with and without vitamin B12. The rats were train-fed for ten months on the same diets. The presence of sodium prop i onate in vitamin B12-deficient basal diets resulted in reduced food intake while BD had the opposite effect. As a result, vitamin B12-deficient rats fed a 5% sodium propionate diet grew less than those fed a 5% BD diet. The metabolism in vivo of BD labeled in carbon-1 (BD-l-cl4) and carbon-4 (BD-4-cl4) were compared to the metabolism of propionate-l-cl4 (PRP-l-cl4) in vitamin B12-deficient and normal rats. Vitamin B12 deficiency reduced the oxidation of sodium propionate but not that of BD, and had no effect on glycogen labeling from BD-l-cl4 and BD-4-cl4. For PRP-l-cl4 however, vitamin B12 deficiency resulted in not only no incorporation of label but liver glycogen levels were very small. On the other hand , when vitamin B12 was present in the diet, the labeling of glycogen from propionate was higher than that from either of the BD-labeled test compounds. Methylmalonic aciduria and urinary loss of ingested activity was higher in vitamin B12-deficient rats fed PRP-l-cl4 than in those fed l abe l ed BD. Nearly all of the urinary activity of vitamin B 1 2-deficient rats fed PRP-l-cl4 was in the form of me t hy l malonic acid (MMA), while little, if any, of the activity was found in the MMA fraction of urine of vita m in B12-deficient rats fed labeled BD. The metabolism in vivo of BD-c14 and BD-3-c14 was investigated in normal rats. About eighty percent of BD was oxidized to carbon dioxide within 32 hours. Its oxidation in the first eight hours was higher when BD was administered intraperitoneally than when it was fed by stomach tube. The loss of ingested activity in the urine expressed as a percentage of total intake and 1,3-BD was higher at the higher doses of BD. However, the activity in urinary BD could not account for all the activity in the urine. A considerable amount of ketone bodies was detected in urine of rats after feeding BD while no detectable ketone bodies were found in the urine of control rats. In addition, relative specific activities of urinary BD and S -hydroxybutyrate were 0.91 and 0.50 respectively. Polarimetry of both purified urinary BD and S -hydroxybutyrate showed that the percentages of (+)- and (-)-isomers of both compounds were 40 and 60% respectively. The metabolism in vitro of BD-3-c14 and DL-S - hydroxybutyrate-4-cl4 were investigated in systems which contained liver slices alone, diaphragm alone or both liver slices plus diaphragm. The oxidation rate of S -hydroxybut y rate was lower in liver slices than in either the diaphragm or the liver slices plus diaphragm systems. Moreover, the rate of oxidation of S -hydrox y- butyrate was highest in the system which included both liver slices and diaphragm. On the other hand, the oxidation rate of BD was lower in the system which had only diaphragm than in the other two systems. However, the rate of BD oxidation was highest in the system - wh ich included both liver slices and diaphragm. Presence of BD gave rise to increased D-(-)- S -hydroxybutyrate and acetoacetate in systems which contained liver slices or liver slices plus diaphragm. In addition, the production rate of D-(-)- S - hydroxybutyric acid was higher than that of acetoacetate in the pre sence of BD, while the opposite was true in its absence. Finally, all the radioactivity in the control incubation media was accounted for by BD-3-cl4, while about 1.5 and 98.5 percent of incubation media activity were recovered in S -hydroxybutyrate and BD peaks, respectively, in incub at ion systems containing liver. The results of this study indicate that 1,3-BD and sodium propionate do not share a common metabolic pathway in the rat. The data suggest, however, that nahapetian-4-1, 3-BD is most probably oxidized to S-hydroxybutyric acid using a "1,3-butanediol dehydrogenase" that is higher in activity in the liver than in the diaphragm. M oreover the (+)-isomer of BD is oxidized at a faster rate than the (-)-isomer, suggesting that the two isomers are oxidized by two different pathways.