Summary
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<0.001) and ALA-dehydratase activity was reduced by 37% (p<0.001). Circulating carbamazepine concentrations correlated negatively with ALA dehydratase (r s=−0.45;p<0.01). Porphobilinogen deaminase and uroporphyrinogen decarboxylase appeared unaffected by carbamazepine treatment. Significant quantitative increases in the urinary excretion of porphobilinogen and total porphyrins (bothp<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.
Similar content being viewed by others
References
Alleman MA, Wilson JHP, van der Berg JWO, Edixhoven-Bosdijk A, van Gastel-Quist (1982) Familial porphyria cutanea tarda: The pattern of porphyrins formed from porphobilinogen by haemolysates. Clin Chem 28: 1144–1147
Anderson PM, Desnick RJ (1982) Porphobilinogen deaminase: Methods and principles of the enzymatic assay. Enzyme 28: 146–157
Berlin A, Schaller KH (1974) European standardised method for the determination of 5-aminolaevulinic acid dehydratase activity in blood. Zeitschr. Klin Chem Klin Biochem 12: 389–390
Boobis AR, Davies DS (1984) Human cytochromes P-450. Xenobiotica 14: 151–185
Brodie MJ (1985) The optimum use of anticonvulsants. Practitioner 229: 921–927
Brodie MJ, Goldberg A (1980) Acute hepatic porphyrias. Clin Haematol 9: 253–272
Brodie MJ, Moore MR, Goldberg A (1977) Enzyme abnormalities in the porphyrias. Lancet 2: 699–701
Brodie MJ, Thompson GG, Moore MR, Beattie AD, Goldberg A (1977) Hereditary coproporphyria: demonstration of the abnormalities in haem biosynthesis in peripheral blood. Q J Med 182: 229–241
Doss M, Schafer HJ (1984) Carbamazepine-induced acute porphyria syndrome. Lancet 1: 1026
Gorchein A, Webber R, Burnett D, Goudie JH (1987) Effect of anticonvulsant drugs on serum delta-aminolaevulinic acid levels in non-porphyric subjects. Br J Clin Pharmacol 24: 847–848
McColl KEL, Moore MR, Thompson GG, Goldberg A (1980) Induction of 5-aminolaevulinic acid synthase in leukocytes of patients on phenytoin therapy — comparison with changes in rat hepatic tissue. Br J Clin Pharmacol 31: 480–484
McGuire GM, Moore MR, Macphee GJA, Goldberg A, Brodie MJ (1985) 5-aminolaevulinate dehydratase and carbamazepine in man and rat. Biochem Soc Trans 13: 205–205
Meredith PA, Moore MR, Campbell BC, Thompson GG, Goldberg A (1978) Delta aminolaevulinic acid metabolism in normal and lead exposed humans. Toxicology 9: 1–9
Moore MR (1980) International review of drugs in acute porphyria. Int J Biochem 12: 1089–1097
Murray GI, Barnes TS, Sewell HF, Ewen SWB, Melvin WT, Burke MD (1988) The immunocytochemical localisation and distribution of cytochrome P-450 in normal human hepatic and extrahepatic tissues with a monoclonal antibody to human cytochrome P-450. Br J Clin Pharmacol 25: 463–475
Park BK (1978) A direct radio-immunoassay for 6β-hydroxycortisol in human urine. J Steroid Biochem 9: 963–966
Park BK (1981) Assessment of urinary 6β-hydroxycortisol as an in vivo index of mixed function oxidase activity. Br J Clin Pharmacol 12: 97–102
Piepkorn MW, Hamernyik P, Labbe RF (1978) Modified erythrocyte uroporphyrinogen-1-synthase assay and its clinical interpretation. Clin Chem 24: 1751–1754
Rajamanickam C, Satyanarayana MR, Padmanaban G (1975) On the sequence of reactions leading to cyt P450 synthesis — effect of drugs J Biol Chem 250: 2305–2310
Rapeport WG, McInnes GT, Forrest GG, Thompson GG, Park BK, Brodie MJ (1983) Hepatic enzyme induction and leukocyte delta aminolaevulinic acid synthase activity: Studies with carbamazepine. Br J Clin Pharmacol 16: 133–137
Rapeport WG, Connell JC, Thompson GG, Moore MR, Brodie MJ (1984) Effect of carbamazepine on haern biosynthesis in man. Eur J Clin Invest 14: 107–110
Rideout JM, Wright DJ, Lim CK, Rinsler MG, Peter TJ (1983) Carbamazepine-induced non-hereditary acute porphyria. Lancet 2: 464
Shanley BC (1983) Carbamazepine-induced non-hereditary acute porphyria. Lancet 1: 1229
Smith AG, De Matteis F (1980) Drugs and the hepatic porphyrias. Clin Haematol 9: 399–425
Strand L, Meyer UA, Felsher BF, Redeker AG, Marver HS (1972) Decreased red cell uroporphyrinogen-1-synthese activity in intermittent acute porphyria. J Clin Invest 51: 2530–2536
Seubert A, Seubert S (1982) High performance liquid chromatographic analysis of porphyrins and their isomers with radial compression columns. Analyt Biochem 124: 303–307
Thompson GG, Small M, Lowe GDO, Forbes CD, Park BK, Scobie G, Brodie MJ (1984) Effect of stanazolol on delta aminolaevulinic acid synthase and hepatic monooxygenase activity in man and rat. Eur J Clin Pharmacol 26: 587–590
Yeung AYL, Rapeport WG, Thompson GG, Macphee GJA, Philip MF, Moore MR, Brodie MJ, Goldberg A (1983) Carbamazepine induced non-hereditary acute porphyria. Lancet 1: 790–792
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
McGuire, G.M., Macphee, G.J.A., Thompson, G.G. et al. The effects of chronic carbamazepine treatment on haem biosynthesis in man and rat. Eur J Clin Pharmacol 35, 241–247 (1988). https://doi.org/10.1007/BF00558260
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00558260