Effects of acute carbamazepine administration on haem metabolism in rat liver.
The effects of acute carbamazepine (CBZ) administration on haem metabolism in rat liver were examined in relation to the mechanism by which it exacerbates hepatic porphyrias. In a screening test for drug exacerbation of porphyria developed in this laboratory, CBZ at a very small dose (1.5 mg/kg, p.o.) behaved as an exacerbator, potentiating the loss of haem utilized by tryptophan pyrrolase (TP; tryptophan 2,3-dioxygenase; L-tryptophan-O2 oxido-reductase, decyclizing; EC 1.13.11.11) and the associated induction of activity of the rate-limiting enzyme of haem biosynthesis, 5-aminolaevulinate synthase (5-ALA-S) caused by the experimental porphyrogen 3,5-diethoxycarbonyl-1,4-dihydrocollidine. A larger dose of CBZ (50 mg/kg, i.p.) induced 5-ALA-S activity by 40-100% at 3 hr. This induction was preceded by an increase in the haem saturation of TP, and was abolished when such an increase was prevented by allopurinol. 5-ALA-S induction by CBZ was not associated with decreased turnover of the enzyme, nor with any significant changes in concentration of the major hepatic haemoprotein, cytochrome P450. It is suggested that CBZ may exacerbate the hepatic porphyrias by inducing 5-ALA-S activity secondarily to an increased utilization of haem by TP.
Morgan
C J
CJ
South Glamorgan Health Authority, Biomedical Research Laboratory, Whitchurch Hospital, Cardiff, U.K.
Badawy
A A
AA
D000624:5-Aminolevulinate Synthetase / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D000493:Allopurinol / Q000494:pharmacology; D000818:Animals; D002220:Carbamazepine / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D056486:Chemical and Drug Induced Liver Injury; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D006418:Heme / Q000378:metabolism*; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D011164:Porphyrias / Q000139:chemically induced; D051381:Rats; D011919:Rats, Inbred Strains; D014366:Tryptophan Oxygenase / Q000037:antagonists & inhibitors
D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D002220:Carbamazepine; D006418:Heme; D000493:Allopurinol; D003577:Cytochrome P-450 Enzyme System; D014366:Tryptophan Oxygenase; D000624:5-Aminolevulinate Synthetase