stilbenes and Drug-Hypersensitivity

Idiosyncratic hypersensitivity reactions with carbamazepine have been postulated to be due to a deficiency of microsomal epoxide hydrolase (HYL1), although this is based on indirect evidence. Using 3H-cis stilbene oxide (0.5 Ci/mmol) as a substrate, we have developed a radiometric HPLC assay sensitive enough to measure the kinetic parameters of HYL1 in lymphocytes. The intra-assay coefficient of variation was 8%. Enzyme activity has been measured in lymphocytes from six carbamazepine hypersensitive patients, six patients on carbamazepine without any adverse effects, and twelve drug-naive healthy volunteers. No significant difference was observed in three kinetic parameters of the enzyme among these three groups. The values for Km, Vmax, and intrinsic clearance ranged from 6.1-89.9 microM, 3.0-23.2 pmoles diol formed/min/mg protein, and 0.147-0.493 microliter/min/mg protein. There was no difference in enzyme activity between patients currently on carbamazepine and healthy volunteers, indicating a lack of induction of lymphocyte HYL1 by carbamazepine. Co-incubation of lymphocytes with 1,1,1-trichloropropene oxide, an inhibitor of hepatic HYL1, resulted in an 82% inhibition of activity, similar to that observed with the hepatic enzyme. The healthy volunteers were genotyped as being either GSTM1 positive (n = 6) or GSTM1 negative (n = 6). This did not affect the kinetic parameters of lymphocyte microsomal epoxide hydrolase. Our results suggest that there is normal HYL1 activity in lymphocytes of hypersensitive patients using cis-stilbene oxide as a substrate.

Topics: Adolescent; Adult; Aged; Anticonvulsants; Carbamazepine; Chromatography, High Pressure Liquid; Drug Hypersensitivity; Enzyme Inhibitors; Epoxide Hydrolases; Female; Glutathione Transferase; Humans; Hydrolysis; Isoenzymes; Kinetics; Lymphocytes; Male; Microsomes; Middle Aged; Radiometry; Stilbenes; Trichloroepoxypropane; Tritium

Topics: ABO Blood-Group System; Amides; Analgesics; Antibodies; Antigens; Aspirin; Benzoates; Drug Hypersensitivity; Dydrogesterone; Erythroblastosis, Fetal; Exchange Transfusion, Whole Blood; Female; Humans; Infant, Newborn; Pregnancy; Rh-Hr Blood-Group System; Sodium; Stilbenes