Phenobarbital does not increase early labeling of bilirubin from 4-[14C]-δ-aminolevulinic acid in man and rat

Abstract

delta-Aminolevulinic acid-4-[14C] and [3H]-bilirubin were administered intravenously to five patients with Gilbert's syndrome and four healthy control subjects on two occasions: before and on days 10 through 14 of a course of phenobarbital (2.5 mg/kg/day). The resulting curves of [3H]-bilirubin and [14C]-bilirubin in plasma were analyzed by computer to determine a number of parameters of physiological interest. As expected, phenobarbital produced a highly significant fall in the plasma concentration of unconjugated bilirubin as a result of a significant increase in hepatic bilirubin clearance in all subjects; plasma bilirubin turnover was unaltered. Surprisingly, the drug produced no change in the incorporation of [14C]-delta-aminolevulinic acid into [14C]-early labeled bilirubin. To explain this unexpected finding, the effects of phenobarbital (75 mg/kg/day for 6 days) on incorporation of [14C]-delta-aminolevulinic acid and 2-[14C]-glycine into [14C]-early labeled bilirubin and on the activity of the enzyme delta-aminolevulinic acid synthase were studied in nonfasted, adult, male Sprague-Dawley rats. At the dose and duration of treatment used, phenobarbital administration increased total hepatic delta-aminolevulinic acid synthase activity and produced a significant increase of 70% in the incorporation of [14C]-glycine into early labeled bilirubin. By contrast, no increase in the incorporation of [14C]-delta-aminolevulinic acid into early labeled bilirubin was observed. These data suggest that delta-aminolevulinic acid is an inappropriate precursor for studies of the rate of heme biosynthesis, presumably because it bypasses delta-aminolevulinic acid synthase, the physiological rate-limiting enzyme in the heme biosynthetic pathway.

Bilirubin Metabolism and Jaundice

“…This means that hepatic hemes contribute no more than ∼12% of plasma bilirubin turnover. Studies documenting a significant discrepancy between the increase in bilirubin labeling from 3 H-or 14 C-labeled heme precursors and total bilirubin production suggest that that actual percentage is appreciably lower [123,124]. On this basis, hepatic heme turnover would have to increase many-fold in order to result in a clinically recognizable increase in the plasma unconjugated bilirubin concentration.…”

Regulatable fatty acid transport mechanisms are central to the pathophysiology of obesity, fatty liver, and metabolic syndrome

“…We used these methods to characterize the functional defects in bilirubin metabolism in Gilbert’s syndrome (14) and the Crigler-Najjar Syndromes (15-17), often leading to improved definitions of these disorders; to gain insights into bilirubin disposition in hemolytic anemias (7-9) and cholestatic liver diseases (18-20), and to clarify the sources of the early labeled peak of bilirubin synthesis (21-26), at the time a very hot topic which has subsequently cooled considerably. In particular, we established that Gilbert’s syndrome was characterized by a reduction of C BR to ~1/3 of normal, and that such a reduction, in the presence of normal LFTs and serum bile acids (27), served as an operational definition of the syndrome, previously a diagnosis of exclusion.…”