Phenobarbital does not increase early labeling of bilirubin from 4-[14C]-delta-aminolevulinic acid in man and rat.
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.
Okuda
H
H
Department of Medicine (Division of Liver Diseases), Mount Sinai School of Medicine, New York, New York 10029.
Tavoloni
N
N
Blaschke
T F
TF
Kiang
C L
CL
Jones
M J
MJ
Waggoner
J G
JG
Sardana
M K
MK
Sassa
S
S
Shrager
R I
RI
Berk
P D
PD
D000622:Aminolevulinic Acid / Q000378:metabolism*; D000818:Animals; D001646:Bile / Q000378:metabolism; D001663:Bilirubin / Q000378:metabolism* / Q000652:urine; D002250:Carbon Radioisotopes; D005998:Glycine / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000033:anatomy & histology; D008297:Male; D009929:Organ Size / Q000187:drug effects; D010634:Phenobarbital / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains
D002250:Carbon Radioisotopes; D000622:Aminolevulinic Acid; D001663:Bilirubin; D005998:Glycine; D010634:Phenobarbital