The nonerythropoietic component of early bilirubin

M. Levitt; B. A. Schacter; A. Zipursky; L. G. Israels

doi:10.1172/JCI105820

The nonerythropoietic component of early bilirubin

M. Levitt, B. A. Schacter, A. Zipursky, and L. G. Israels

Published June 1, 1968 - More info

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Abstract

The early labeled bilirubin consists of two primary components. The more rapidly synthesized of the two is independent of erythropoiesis (nonerythropoietic), whereas the second fraction is related to red cell production (erythyropoietic). The present studies concern the origin of the nonerythropoietic component.

The nonerythropoietic, early labeled bilirubin was studied in bile fistula rats with (delta ALA)-4-¹⁴C delta aminolevulinic acid and glycine-2-¹⁴C as precursors. That nephrectomy did not reduce the size of this component despite the large and rapidly turning over pool of renal heme suggests that this pool may be of minor importance in its production. Intoxication with lead to a level that reduced hepatic heme synthesis was associated with a decrease in early bilirubin formation. The synthesis of this bilirubin was assessed in animals with phenobarbital-induced heme protein and cycloheximide-suppressed protein synthesis. Rats pretreated with phenobarbital at a dose level of 60 mg/kg with induction of cytochrome P-450 synthesis showed a minor increase in early labeling when glycine-2-¹⁴C but not when delta ALA-4-¹⁴C was used as precursor. Rats given cycloheximide at a dose level that markedly reduced hepatic protein and cytochrome P-450 synthesis but allowed heme synthesis to continue at 60% of its pretreatment level synthesized normal or increased amounts of early bilirubin from delta ALA-4-¹⁴C. Allylisopropylacetamide intoxication caused little change in early bilirubin formation, whereas aminotriazole given at a time after maximal hepatic heme labeling produced a small but significant increase in the appearance of labeled bilirubin.

These findings indicate that early bilirubin production is little influenced by increased hepatic porphyrin synthesis or by changes in the rapidly turning over heme protein P-450. A minimal increase attends catalase inactivation by aminotriazole. Normal or increased synthesis takes place in the presence of suppression of protein synthesis. This finding suggests that the nonerythropoietic early bilirubin may itself consist of two subcomponents. The first of these may arise from free tissue heme or its precursors, and the second may derive from the turnover of the heme proteins. The first subcomponent may serve as a regulatory mechanism for the removal of heme synthesized in excess of its protein acceptor. A composite scheme is proposed for the origin of the total early bilirubin from heme compartments in tissue and marrow.