title: Protoporphyrinaemia and decreased activities of 5-aminolevulinic acid dehydrase and uroporphyrinogen I synthetase in erythrocytes of a Vitamin B6-deficient epileptic boy given valproic acid and carbamazepine.
abstract: Carbamazepine (CBMZP) has been implicated as an inhibitor of the activities of 5-aminolaevulinic acid dehydratase (ALA-D) and uroporphyrinogen I synthetase (URO-S). In an epileptic boy undergoing long-term treatment with valproic acid (VPA), 1.3 g/d, CBMZP, 0.9 g/d and folic acid, 7.5 mg/d, decreased activities of ALA-D and URO-S coincided with increased levels of erythrocyte protoporphyrin (EP) in the absence of Pb poisoning, iron depletion and erythropoietic protoporphyria. A progressive fall in plasma pyridoxal 5'-phosphate (B6-P) to 7.7 nmol/L (lower reference limit, 14.6 nmol/L) prompted implementation of pyridoxine HCl (B6-HCl), 87.5 mg/d followed by administration of both B6-HCl and preformed B6-P (50 mg/d each). This permitted the eventual withdrawal of VPA and a net reduction of CBMZP to 450 mg/d. During these manipulations, ALA-D and URO-S activities, EP and urinary porphyrins and their precursors were measured serially. An assay system utilizing red cell ALA-D for generation of porphobilinogen (PBG) from added ALA at pH 7.4 was used for determination of ALA-D and URO-S activities in separate aliquots of the same assay mixture both in the absence and presence of Zn and dithiothreitol (DTT). One unit (U) for ALA-D = 1 nmol PBG/L RBC/s; for URO-S = 1 nmol porphyrin/L/s; minimum normal level for ALA-D = 135 U; for URO-S = 6 U. B6-HCl alone entailed increases in ALA-D and URO-S prior to any reduction of CBMZP. After administration of both B6-HCl and B6-P and withdrawal of VPA, the overall increase in ALA-D was from 54.59 to 197.2 U (-Zn; -DTT) and from 50.76 to 217.3 U (+Zn; +DTT). The overall increase in URO-S was from 2.67 to 8.90 U (-Zn; -DTT) and from 3.02 to 8.66 U (+Zn; +DTT). During stepwise reduction of VPA, EP remained elevated to values as high as 2.48 mumol/L (upper reference limit, 1.33 mumol/L). Only after permanent withdrawal of VPA did concentrations of EP fall to normal levels. Values for porphyrins and their precursors in urine were normal throughout. Since both VPA and B6-P are strongly protein-bound, it is suggested that VPA displaced B6-P from protective protein binding sites and that the resulting deficit in B6-P (rather than CBMZP) reduced ALA-D and URO-S activities via primary reduction of ALA-synthetase activity. Increases in EP emerge as a hitherto unappreciated effect of VPA warranting further investigation.
authors.affiliation: Department of Biochemistry, University of Western Ontario, Canada.
authors.forename: H L
authors.initials: HL
authors.lastname: Haust
authors.forename: H C
authors.initials: HC
authors.lastname: Poon
authors.forename: R
authors.initials: R
authors.lastname: Carson
authors.forename: C
authors.initials: C
authors.lastname: VanDeWetering
authors.forename: F
authors.initials: F
authors.lastname: Peter
mesh_terms: D000642:Ammonia-Lyases / Q000097:blood*; D002220:Carbamazepine / Q000009:adverse effects*; D002852:Chromatography, Ion Exchange; D004827:Epilepsy / Q000097:blood / Q000150:complications*; D004912:Erythrocytes / Q000201:enzymology*; D005492:Folic Acid / Q000627:therapeutic use; D006801:Humans; D011163:Hydroxymethylbilane Synthase / Q000097:blood*; D007223:Infant; D007854:Lead / Q000097:blood; D008137:Longitudinal Studies; D008297:Male; D000623:Porphobilinogen Synthase / Q000097:blood*; D011166:Porphyrins / Q000652:urine; D011524:Protoporphyrins / Q000097:blood; D013050:Spectrometry, Fluorescence; D013054:Spectrophotometry, Atomic; D014635:Valproic Acid / Q000009:adverse effects*; D026681:Vitamin B 6 Deficiency / Q000097:blood* / Q000188:drug therapy
chemical_list: D011166:Porphyrins; D011524:Protoporphyrins; D007854:Lead; D002220:Carbamazepine; D014635:Valproic Acid; D005492:Folic Acid; D011163:Hydroxymethylbilane Synthase; D000623:Porphobilinogen Synthase; D000642:Ammonia-Lyases