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Lack of low Km diazepam N-demethylase in livers of poor metabolizers for S-mephenytoin 4'-hydroxylation.
Pharmacogenetics. 1994 Dec; 4(6):323-31.P

Abstract

Metabolism of diazepam was studied in vitro to identify the forms of cytochrome P450 (CYP) responsible for N-demethylation (nordazepam formation) and 3-hydroxylation (temazepam formation), using liver microsomes obtained from extensive (EM) and poor metabolizers (PM) for S-mephenytoin 4'-hydroxylation. Involvement of at least two P450 forms in diazepam N-demethylation was suggested by a biphasic pattern in Lineweaver-Burk and Eadie-Hofstee plots from the EM, whereas a monophasic pattern was observed from the PM liver microsomes. The kinetic parameters for the N-demethylation in the EM group were: Km 1, 19.4 +/- 0.4 microM; Vmax 1, 0.27 +/- 0.04 nmol min-1 per mg protein; Km 2, 346 +/- 34 microM; Vmax2, 1.82 +/- 0.63 nmol min-1 per mg protein (n = 3, mean +/- SD). The PM group showed the mean values of Km and Vmax (Km, 319 +/- 30 microM; Vmax, 1.49 +/- 0.62 nmol min-1 per mg protein) (n = 3) similar to those of Km2 and Vmax2 in the EM group. An antibody raised against CYP2C9 (anti-human CYP2C) strongly inhibited diazepam N-demethylation in EM liver microsomes at a low substrate concentration (20 microM). However, the anti-human CYP2C showed no clear inhibition of N-demethylation in EM liver microsomes at a high substrate concentration (200 microM). Diazepam N-demethylation in PM liver microsomes was not clearly inhibited by the anti-human CYP2C at either the low or high substrate concentrations. These data suggest that different P450 forms mediated diazepam N-demethylation in EM and PM liver microsomes, respectively.(

ABSTRACT

TRUNCATED AT 250 WORDS)

Authors+Show Affiliations

Department of Pharmacology, School of Medicine, Keio University, Tokyo, Japan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

7704038

Citation

Yasumori, T, et al. "Lack of Low Km Diazepam N-demethylase in Livers of Poor Metabolizers for S-mephenytoin 4'-hydroxylation." Pharmacogenetics, vol. 4, no. 6, 1994, pp. 323-31.
Yasumori T, Li QH, Yamazoe Y, et al. Lack of low Km diazepam N-demethylase in livers of poor metabolizers for S-mephenytoin 4'-hydroxylation. Pharmacogenetics. 1994;4(6):323-31.
Yasumori, T., Li, Q. H., Yamazoe, Y., Ueda, M., Tsuzuki, T., & Kato, R. (1994). Lack of low Km diazepam N-demethylase in livers of poor metabolizers for S-mephenytoin 4'-hydroxylation. Pharmacogenetics, 4(6), 323-31.
Yasumori T, et al. Lack of Low Km Diazepam N-demethylase in Livers of Poor Metabolizers for S-mephenytoin 4'-hydroxylation. Pharmacogenetics. 1994;4(6):323-31. PubMed PMID: 7704038.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Lack of low Km diazepam N-demethylase in livers of poor metabolizers for S-mephenytoin 4'-hydroxylation. AU - Yasumori,T, AU - Li,Q H, AU - Yamazoe,Y, AU - Ueda,M, AU - Tsuzuki,T, AU - Kato,R, PY - 1994/12/1/pubmed PY - 1994/12/1/medline PY - 1994/12/1/entrez SP - 323 EP - 31 JF - Pharmacogenetics JO - Pharmacogenetics VL - 4 IS - 6 N2 - Metabolism of diazepam was studied in vitro to identify the forms of cytochrome P450 (CYP) responsible for N-demethylation (nordazepam formation) and 3-hydroxylation (temazepam formation), using liver microsomes obtained from extensive (EM) and poor metabolizers (PM) for S-mephenytoin 4'-hydroxylation. Involvement of at least two P450 forms in diazepam N-demethylation was suggested by a biphasic pattern in Lineweaver-Burk and Eadie-Hofstee plots from the EM, whereas a monophasic pattern was observed from the PM liver microsomes. The kinetic parameters for the N-demethylation in the EM group were: Km 1, 19.4 +/- 0.4 microM; Vmax 1, 0.27 +/- 0.04 nmol min-1 per mg protein; Km 2, 346 +/- 34 microM; Vmax2, 1.82 +/- 0.63 nmol min-1 per mg protein (n = 3, mean +/- SD). The PM group showed the mean values of Km and Vmax (Km, 319 +/- 30 microM; Vmax, 1.49 +/- 0.62 nmol min-1 per mg protein) (n = 3) similar to those of Km2 and Vmax2 in the EM group. An antibody raised against CYP2C9 (anti-human CYP2C) strongly inhibited diazepam N-demethylation in EM liver microsomes at a low substrate concentration (20 microM). However, the anti-human CYP2C showed no clear inhibition of N-demethylation in EM liver microsomes at a high substrate concentration (200 microM). Diazepam N-demethylation in PM liver microsomes was not clearly inhibited by the anti-human CYP2C at either the low or high substrate concentrations. These data suggest that different P450 forms mediated diazepam N-demethylation in EM and PM liver microsomes, respectively.(ABSTRACT TRUNCATED AT 250 WORDS) SN - 0960-314X UR - https://www.unboundmedicine.com/medline/citation/7704038/Lack_of_low_Km_diazepam_N_demethylase_in_livers_of_poor_metabolizers_for_S_mephenytoin_4'_hydroxylation_ L2 - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&PAGE=linkout&SEARCH=7704038.ui DB - PRIME DP - Unbound Medicine ER -