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Identification of human CYP isoforms involved in the metabolism of propranolol enantiomers--N-desisopropylation is mediated mainly by CYP1A2.
Br J Clin Pharmacol. 1995 Apr; 39(4):421-31.BJ

Abstract

1. Studies using human liver microsomes and six recombinant human CYP isoforms (i.e. CYP1A2, 2A6, 2B6, 2D6, 2E1 and 3A4) were performed to identify the cytochrome P450 (CYP) isoform(s) involved in the ring 4-hydroxylation and side-chain N-desisopropylation of propranolol enantiomers in humans. 2. alpha-Naphthoflavone and 7-ethoxyresorufin (selective inhibitors of CYP1A1/2) inhibited the N-desisopropylation of R- and S-propranolol by human liver microsomes by 20 and 40%, respectively, while quinidine (a selective inhibitor of CYP2D6) abolished the 4-hydroxylation of both propranolol enantiomers almost completely. In contrast, sulphaphenazole (CYP2C8/9 inhibitor), S-mephenytoin (CYP2C19 inhibitor), troleandomycin (CYP3A3/4 inhibitor) and diethyldithiocarbamate (CYP2E1 inhibitor) elicited only weak inhibitory effects on propranolol metabolism via the two measured metabolic pathways. 3. Significant (P < 0.01) correlations were observed between the microsomal N-desisopropylation of both propranolol enantiomers and that for the O-deethylation of phenacetin among the 11 different human liver microsome samples (r = 0.98 and 0.77 for R- and S-propranolol, respectively). A marginally significant (r = 0.60, P congruent to 0.05) correlation was also observed between N-desisopropylation of S-, but not of R-propranolol and the 4'-hydroxylation of S-mephenytoin. No significant correlations were observed between the N-desisopropylation of propranolol enantiomers and the 2-hydroxylation of desipramine, the hydroxylation of tolbutamide or the 6 beta-hydroxylation of testosterone. 4. Significant (P < 0.01) correlations were observed between the microsomal 4-hydroxylation of R- and S-propranolol and the 2-hydroxylation of desipramine (r = 0.85 and 0.98, respectively). A weak (r = 0.66), albeit significant (P < 0.05) correlation was observed between the 4-hydroxylation of R-, but not of S-propranolol and the hydroxylation of tolbutamide. No significant correlations were observed between the 4-hydroxylation of propranolol enantiomers and the oxidation of other substrates for CYP1A2, 2C19, and 3A3/4. 5. Recombinant human CYP1A2 and CYP2D6 exhibited comparable catalytic activity with respect to the N-desisopropylation of both propranolol enantiomers; only expressed CYP2D6 exhibited a marked catalytic activity with respect to the 4-hydroxylation of both propranolol enantiomers.(

ABSTRACT

TRUNCATED AT 400 WORDS)

Authors+Show Affiliations

Department of Clinical Pharmacology, International Medical Center of Japan, Tokyo.No 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

7640150

Citation

Yoshimoto, K, et al. "Identification of Human CYP Isoforms Involved in the Metabolism of Propranolol enantiomers--N-desisopropylation Is Mediated Mainly By CYP1A2." British Journal of Clinical Pharmacology, vol. 39, no. 4, 1995, pp. 421-31.
Yoshimoto K, Echizen H, Chiba K, et al. Identification of human CYP isoforms involved in the metabolism of propranolol enantiomers--N-desisopropylation is mediated mainly by CYP1A2. Br J Clin Pharmacol. 1995;39(4):421-31.
Yoshimoto, K., Echizen, H., Chiba, K., Tani, M., & Ishizaki, T. (1995). Identification of human CYP isoforms involved in the metabolism of propranolol enantiomers--N-desisopropylation is mediated mainly by CYP1A2. British Journal of Clinical Pharmacology, 39(4), 421-31.
Yoshimoto K, et al. Identification of Human CYP Isoforms Involved in the Metabolism of Propranolol enantiomers--N-desisopropylation Is Mediated Mainly By CYP1A2. Br J Clin Pharmacol. 1995;39(4):421-31. PubMed PMID: 7640150.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Identification of human CYP isoforms involved in the metabolism of propranolol enantiomers--N-desisopropylation is mediated mainly by CYP1A2. AU - Yoshimoto,K, AU - Echizen,H, AU - Chiba,K, AU - Tani,M, AU - Ishizaki,T, PY - 1995/4/1/pubmed PY - 1995/4/1/medline PY - 1995/4/1/entrez SP - 421 EP - 31 JF - British journal of clinical pharmacology JO - Br J Clin Pharmacol VL - 39 IS - 4 N2 - 1. Studies using human liver microsomes and six recombinant human CYP isoforms (i.e. CYP1A2, 2A6, 2B6, 2D6, 2E1 and 3A4) were performed to identify the cytochrome P450 (CYP) isoform(s) involved in the ring 4-hydroxylation and side-chain N-desisopropylation of propranolol enantiomers in humans. 2. alpha-Naphthoflavone and 7-ethoxyresorufin (selective inhibitors of CYP1A1/2) inhibited the N-desisopropylation of R- and S-propranolol by human liver microsomes by 20 and 40%, respectively, while quinidine (a selective inhibitor of CYP2D6) abolished the 4-hydroxylation of both propranolol enantiomers almost completely. In contrast, sulphaphenazole (CYP2C8/9 inhibitor), S-mephenytoin (CYP2C19 inhibitor), troleandomycin (CYP3A3/4 inhibitor) and diethyldithiocarbamate (CYP2E1 inhibitor) elicited only weak inhibitory effects on propranolol metabolism via the two measured metabolic pathways. 3. Significant (P < 0.01) correlations were observed between the microsomal N-desisopropylation of both propranolol enantiomers and that for the O-deethylation of phenacetin among the 11 different human liver microsome samples (r = 0.98 and 0.77 for R- and S-propranolol, respectively). A marginally significant (r = 0.60, P congruent to 0.05) correlation was also observed between N-desisopropylation of S-, but not of R-propranolol and the 4'-hydroxylation of S-mephenytoin. No significant correlations were observed between the N-desisopropylation of propranolol enantiomers and the 2-hydroxylation of desipramine, the hydroxylation of tolbutamide or the 6 beta-hydroxylation of testosterone. 4. Significant (P < 0.01) correlations were observed between the microsomal 4-hydroxylation of R- and S-propranolol and the 2-hydroxylation of desipramine (r = 0.85 and 0.98, respectively). A weak (r = 0.66), albeit significant (P < 0.05) correlation was observed between the 4-hydroxylation of R-, but not of S-propranolol and the hydroxylation of tolbutamide. No significant correlations were observed between the 4-hydroxylation of propranolol enantiomers and the oxidation of other substrates for CYP1A2, 2C19, and 3A3/4. 5. Recombinant human CYP1A2 and CYP2D6 exhibited comparable catalytic activity with respect to the N-desisopropylation of both propranolol enantiomers; only expressed CYP2D6 exhibited a marked catalytic activity with respect to the 4-hydroxylation of both propranolol enantiomers.(ABSTRACT TRUNCATED AT 400 WORDS) SN - 0306-5251 UR - https://www.unboundmedicine.com/medline/citation/7640150/Identification_of_human_CYP_isoforms_involved_in_the_metabolism_of_propranolol_enantiomers__N_desisopropylation_is_mediated_mainly_by_CYP1A2_ L2 - https://onlinelibrary.wiley.com/resolve/openurl?genre=article&amp;sid=nlm:pubmed&amp;issn=0306-5251&amp;date=1995&amp;volume=39&amp;issue=4&amp;spage=421 DB - PRIME DP - Unbound Medicine ER -