The effects of chronic carbamazepine treatment of haem biosynthesis in man and rat.
The anticonvulsant drug carbamazepine has been reported to produce a condition clinically and biochemically similar to acute intermittent porphyria (AIP). We have determined the effect of chronic carbamazepine treatment on the activities of the enzymes of haem biosynthesis in circulating blood cells and on the urinary excretion of porphyrins and their precursors in 53 epileptic patients receiving monotherapy and in 42 age- and sex-matched controls. In the patients the mean activity of leucocyte 5-aminolaevulinic acid (ALA) synthase, the rate-limiting enzyme of the pathway, was 218% of control values (p less than 0.001) and ALA-dehydratase activity was reduced by 37% (p less than 0.001). Circulating carbamazepine concentrations correlated negatively with ALA dehydratase (rs = -0.45; p less than 0.01). Porphobilinogen deaminase and uroporphyrinogen decarboxylase appeared unaffected by carbamazepine treatment. Significant quantitative increases in the urinary excretion of porphobilinogen and total porphyrins (both p less than 0.05) accompanied the changes in enzyme activity. Similar dose-dependent effects on ALA synthase and ALA dehydratase were shown to occur in rats treated for 5 days with 3 different doses of carbamazepine. These findings further support the porphyrinogenicity of carbamazepine, but the pattern of enzyme alteration differs from that found in AIP.
McGuire
G M
GM
University Department of Medicine, Gardiner Institute, Western Infirmary, Glasgow, Scotland.
Macphee
G J
GJ
Thompson
G G
GG
Park
B K
BK
Moore
M R
MR
Brodie
M J
MJ
D000624:5-Aminolevulinate Synthetase / Q000378:metabolism*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000622:Aminolevulinic Acid / Q000652:urine; D000642:Ammonia-Lyases / Q000378:metabolism*; D000818:Animals; D002220:Carbamazepine / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D006418:Heme / Q000096:biosynthesis*; D006801:Humans; D011163:Hydroxymethylbilane Synthase / Q000378:metabolism*; D007962:Leukocytes / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D011162:Porphobilinogen / Q000652:urine; D000623:Porphobilinogen Synthase / Q000378:metabolism*; D011166:Porphyrins / Q000652:urine; D051381:Rats; D011919:Rats, Inbred Strains
D011166:Porphyrins; D002220:Carbamazepine; D006418:Heme; D011162:Porphobilinogen; D000622:Aminolevulinic Acid; D000624:5-Aminolevulinate Synthetase; D011163:Hydroxymethylbilane Synthase; D000623:Porphobilinogen Synthase; D000642:Ammonia-Lyases