Drug hepatotoxicity is partially determined by genetic factors involved in
drug metabolism, which may involve the
debrisoquine oxidation polymorphism mediated by
cytochrome (
CYP) 2D6. The purpose of this study was to assess the relationship between
drug hepatotoxicity and another genetic polymorphism of
drug oxidation, namely that of S-
mephenytoin metabolism mediated by CYP2CMP.
Mephenytoin hydroxylation capacity was assessed by a hydroxylation index in 24 patients with
drug-induced hepatitis and in 23 healthy controls. Hydroxylation index was calculated as the ratio of S-
mephenytoin dose to the (0-10 h) urinary excretion of
4-hydroxymephenytoin after
oral administration of 100 mg racemic
mephenytoin. The test was performed following the patient's recovery. In three patients,
hepatitis was related to Atrium, a
drug containing
phenobarbital,
febarbamate and
difebarbamate. The mean hydroxylation index (+/- SD) value in patients with Atrium
hepatitis (12.4 +/- 8.3) was markedly higher than that found in healthy controls (1.8 +/- 0.4) or in patients with other
drug-induced hepatitis (2.5 +/- 3.3). Mean hydroxylation index values were similar in the two latter groups. Considered individually, oxidation capacity was low (hydroxylation index > 9) in two of the three patients with Atrium
hepatitis and intermediate (hydroxylation index between 4 and 9) in the third patient. In contrast, all 23 healthy subjects exhibited a high oxidation capacity (hydroxylation index < 4). In the 21 patients with other
drug-induced hepatitis, oxidation capacity was high in 19 subjects, intermediate in one subject with
chlorpromazine hepatitis, and low in one subject with
dapsone hepatitis.(ABSTRACT TRUNCATED AT 250 WORDS)