rifampin and Hyperbilirubinemia--Hereditary

Studies in 14 patients with unconjugated hyperbilirubinaemia caused by Gilbert's syndrome have revealed abnormalities of the enzymes of haem biosynthesis measured in peripheral blood cells. The activity of the penultimate enzyme of haem biosynthesis protoporphyrinogen (PROTO) oxidase was reduced at 3.1 +/- 2.6 nmol PROTO/g protein/h (mean +/- ISD) compared with 8.2 +/- 5.1 in controls (p less than 0.005). This was associated with a compensatory increase in the activity of the initial and rate controlling enzyme of the pathway delta-aminolaevulinic acid (ALA) synthase at 866 +/- 636 nmol ALA/g/protein/h compared with 156 +/- 63 in controls (p less than 0.001). Unlike variegate porphyria in which there is a genetic deficiency of PROTO oxidase there was no increased excretion of porphyrins or their precursors in Gilbert's syndrome. Accentuation and subsequent correction of the unconjugated hyperbilirubinaemia with rifampicin produced reciprocal changes in PROTO oxidase activity indicating that bilirubin may be inhibiting the activity of this enzyme.

Topics: 5-Aminolevulinate Synthetase; Adult; Bilirubin; Female; Flavoproteins; Gilbert Disease; Heme; Humans; Hyperbilirubinemia, Hereditary; Male; Middle Aged; Mitochondrial Proteins; Oxidoreductases; Oxidoreductases Acting on CH-CH Group Donors; Porphyrias; Porphyrins; Protoporphyrinogen Oxidase; Rifampin

Topics: Adolescent; Adult; Aged; Bilirubin; Child; Fasting; Female; Gilbert Disease; Humans; Hyperbilirubinemia, Hereditary; Male; Middle Aged; Rifampin

Topics: Adult; Bilirubin; Evaluation Studies as Topic; Female; Gilbert Disease; Humans; Hyperbilirubinemia, Hereditary; Male; Niacin; Rifampin

The value of phenobarbital in the treatment of free bilirubin icterus is demonstrated by a series of clinical experiments in which the drug was administered to patients with bilirubinaemia, even at high levels, the situation being brought back to normal within about two weeks. The percentage excreted with the urine in a conjugated form of various drugs proved higher in subjects treated with phenobarbital than in controls, thus proving that the drug acts as an enzymic inductor. Moreover it is ineffective in patients genetically lacking in the capacity to synthesize glycuronyltransferase. The induction of this latter enzyme, however, does not exhaust the effects of the barbiturate for it has been shown that phenobarbital is capable of speeding up the disappearance of exogenous bilirubin from the plasma in animals, of stimulating bile flow and increasing uptake of the pigment by the liver. The increase in bile flow is of the order of 30% and takes place by way of a modification in the flow fraction independent of bile salts. It would also appear that the drug is capable of increasing the activity of 7-alpha-hydroxylase, an enzyme that represents the rate limiting step in the synthesis of biliary salts. Other drugs commonly used in the treatment of free bilirubin icterus such as ethanol, rifampicin and uridindiphosphoglucose are considered. Finally the case of a female patient who from birth had presented persistent free bilirubin icterus of about 8 mg% is reported. After 14 days treatment with phenobarbital (100 mg X 2) blood levels of the pigment had returned to normal.

Topics: Adult; Enzyme Induction; Female; Gilbert Disease; Glucuronates; Humans; Hyperbilirubinemia, Hereditary; Mixed Function Oxygenases; Phenobarbital; Rifampin; Transferases