Drug-induced pertubation of the aminothiol redox-status in patients with epilepsy: improvement by B-vitamins.
OBJECTIVE
Patients with epilepsy have excess morbidity and mortality due to ischemic cardiovascular disease. Many of these patients have elevated concentrations of plasma total homocysteine (Hcy), which is an acknowledged risk factor for cardiovascular disease, venous thromboembolic disease, foetal malformations and dementia. Hyperhomocysteinemia may have negative effects through mechanisms involving oxidative damage. In the present study, we have investigated the aminothiol redox-status in patients on antiepileptic drugs. Thereafter, in a subset of patients with elevated total Hcy, we evaluated the effect of B-vitamin therapy.


METHODS
In the first part of the study, 101 patients on antiepileptic drugs were compared with 101 matched healthy controls. The redox-species of Hcy, cysteine and cysteinylglycine, the major aminothiols in plasma, were analyzed by high-performance liquid chromatography (HPLC). Hyperhomocysteinemia was defined as fasting total Hcy above 12 micromol/L and/or post-methionine load concentrations above 38 micromol/L. In the second part of the study, 33 patients identified with hyperhomocysteinemia were supplemented with three B-vitamins for 30 days; folic acid (B9), pyridoxine (B6) and riboflavin (B2).


RESULTS
All redox-species of Hcy were significantly elevated in the patients, except the fasting concentrations of reduced Hcy (p=0.09). The reduced/total ratio of cysteine in fasting plasma was lower in the patients than in the controls: 5.20% vs. 6.19%, respectively (p=0.006). After 30 days of B-vitamin supplementation, the plasma concentrations of reduced, oxidized and protein-bound Hcy species were significantly lowered by 17%, 22% and 28%, respectively. The reduced/total ratio of cysteine rose from 4.9% to 7.9% (p=0.007).


CONCLUSIONS
Patients on antiepileptic drugs have abnormal aminothiol redox-status associated with hyperhomocysteinemia. This is similar to findings in patients with cardiovascular disease. B-vitamin supplementation partially corrects the abnormal aminothiol redox-status. Possibly, B-vitamin supplementation may be useful in drug-induced hyperhomocysteinemia.
Apeland
Terje
T
Department of Medicine, Stavanger University Hospital, Stavanger, Norway. apeland@online.no
Frøyland
Elin S
ES
Kristensen
Ole
O
Strandjord
Roald E
RE
Mansoor
Mohammad A
MA
D000328:Adult; D000927:Anticonvulsants / Q000009:adverse effects* / Q000627:therapeutic use; D002220:Carbamazepine / Q000009:adverse effects / Q000627:therapeutic use; D016022:Case-Control Studies; D003545:Cysteine / Q000097:blood; D004151:Dipeptides / Q000097:blood; D004341:Drug Evaluation; D004827:Epilepsy / Q000188:drug therapy / Q000378:metabolism*; D005260:Female; D005492:Folic Acid / Q000008:administration & dosage / Q000627:therapeutic use*; D006801:Humans; D020138:Hyperhomocysteinemia / Q000139:chemically induced / Q000188:drug therapy*; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D008715:Methionine; D010084:Oxidation-Reduction; D010634:Phenobarbital / Q000009:adverse effects / Q000627:therapeutic use; D010672:Phenytoin / Q000009:adverse effects / Q000627:therapeutic use; D011324:Primidone / Q000009:adverse effects / Q000627:therapeutic use; D011736:Pyridoxine / Q000008:administration & dosage / Q000627:therapeutic use*; D012256:Riboflavin / Q000008:administration & dosage / Q000627:therapeutic use*; D014635:Valproic Acid / Q000009:adverse effects / Q000627:therapeutic use; D014804:Vitamin B Deficiency / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy
D000927:Anticonvulsants; D004151:Dipeptides; D011324:Primidone; D002220:Carbamazepine; C028505:cysteinylglycine; D014635:Valproic Acid; D010672:Phenytoin; D005492:Folic Acid; D008715:Methionine; D003545:Cysteine; D011736:Pyridoxine; D012256:Riboflavin; D010634:Phenobarbital