PT  - JOURNAL ARTICLE
AU  - F Marre
AU  - G Fabre
AU  - B Lacarelle
AU  - M Bourrie
AU  - J Catalin
AU  - Y Berger
AU  - R Rahmani
AU  - J P Cano
TI  - Involvement of the cytochrome P-450IID subfamily in minaprine 4-hydroxylation by human hepatic microsomes.
DP  - 1992 Mar 01
TA  - Drug Metabolism and Disposition
PG  - 316--321
VI  - 20
IP  - 2
4099  - http://dmd.aspetjournals.org/content/20/2/316.short
4100  - http://dmd.aspetjournals.org/content/20/2/316.full
SO  - Drug Metab Dispos1992 Mar 01; 20
AB  - 4-Hydroxylation of minaprine was measured on microsomal fractions prepared from 25 different human liver samples. In vitro formation of 4-hydroxyminaprine exhibited a large interindividual variability. Indeed, minaprine 4-hydroxylase activity ranged between 0.033 and 0.421 nmol/min/mg microsomal protein. Two samples presented a particularly low enzyme activity. Minaprine 4-hydroxylation followed Michaelis-Menten kinetics with KM and Vmax values of 5.26 microM and 0.478 nmol/min/mg microsomal protein, respectively, for one particular representative sample. The effects of various compounds (substrates or inhibitors of cytochrome P-450 isoforms) on 4-hydroxyminaprine formation were investigated. Selective substrates for P-450IA [benzo(a)pyrene, theophylline, and phenacetin], IIC (hexobarbital), IIE (aniline), and IIIA (erythromycin, nifedipine, and troleandomycin) cytochrome subfamilies did not inhibit 4-hydroxyminaprine formation. The nonspecific cytochrome P-450 inhibitor, cimetidine, slightly inhibited minaprine 4-hydroxylation. The classical substrates of the P-450IID cytochrome subfamily (debrisoquine, propranolol, and sparteine) inhibited minaprine 4-hydroxylation, as did the known P-450IID specific inhibitor, quinidine. These compounds inhibited minaprine 4-hydroxylase with Ki values of 16.5 (debrisoquine), 14.4 (propranolol), 61.9 (sparteine), and 0.146 microM (quinidine). 4-Hydroxyminaprine formation rate was shown not to be correlated with the activity of both erythromycin N-demethylase (r = 0.29, non-significant) and aniline hydroxylase (r = -0.15, NS). In contrast, minaprine 4-hydroxylase was well correlated with both debrisoquine 4-hydroxylase activity (r = 0.501, p less than 0.05) and immunoquantified cytochrome P-450IID6 (r = 0.579, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)